Virtual clinical QT exposure-response studies - A translational computational approach.

BACKGROUND AND PURPOSE: A recent paradigm shift in proarrhythmic risk assessment suggests that the integration of clinical, non-clinical, and computational evidence can be used to reach a comprehensive understanding of the proarrhythmic potential of drug candidates. While current computational methodologies focus on predicting the incidence of proarrhythmic events after drug administration, the objective of this study is to predict concentration-response relationships of QTc as a clinical endpoint. EXPERIMENTAL APPROACH: Full heart computational models reproducing human cardiac populations were created to predict the concentration-response relationship of changes in the QT interval as recommended for clinical trials. The concentration-response relationship of the QT-interval prolongation obtained from the computational cardiac population was compared against the relationship from clinical trial data for a set of well-characterized compounds: moxifloxacin, dofetilide, verapamil, and ondansetron. KEY RESULTS: Computationally derived concentration-response relationships of QT interval changes for three of the four drugs had slopes within the confidence interval of clinical trials (dofetilide, moxifloxacin and verapamil) when compared to placebo-corrected concentration-ΔQT and concentration-ΔQT regressions. Moxifloxacin showed a higher intercept, outside the confidence interval of the clinical data, demonstrating that in this example, the standard linear regression does not appropriately capture the concentration-response results at very low concentrations. The concentrations corresponding to a mean QTc prolongation of 10 ms were consistently lower in the computational model than in clinical data. The critical concentration varied within an approximate ratio of 0.5 (moxifloxacin and ondansetron) and 1 times (dofetilide, verapamil) the critical concentration observed in human clinical trials. Notably, no other in silico methodology can approximate the human critical concentration values for a QT interval prolongation of 10 ms. CONCLUSION AND IMPLICATIONS: Computational concentration-response modelling of a virtual population of high-resolution, 3-dimensional cardiac models can provide comparable information to clinical data and could be used to complement pre-clinical and clinical safety packages. It provides access to an unlimited exposure range to support trial design and can improve the understanding of pre-clinical-clinical translation.

Performance assessment of an electrostatic filter-diverter stent cerebrovascular protection device. Is it possible not to use anticoagulants in atrial fibrilation elderly patients?

Stroke is the second leading cause of death worldwide. Nearly two-thirds of strokes are produced by cardioembolisms, and half of cardioembolic strokes are triggered by Atrial Fibrillation (AF), the most common type of arrhythmia. A more recent cause of cardioembolisms is Transcatheter Aortic Valve Replacements (TAVRs), which may onset post-procedural adverse events such as stroke and Silent Brain Infarcts (SBIs), for which no definitive treatment exists, and which will only get worse as TAVRs are implanted in younger and lower risk patients. It is well known that some specific characteristics of elderly patients may lower the safety and efficacy of anticoagulation therapy, making it a real urgency to find alternative therapies. We propose a device consisting of a strut structure placed at the base of the treated artery to model the potential risk of cerebral embolisms caused by dislodged debris of varying sizes. This work analyzes a design based on a patented medical device, intended to block cardioembolisms from entering the cerebrovascular system, with a particular focus on AF, and potentially TAVR patients. The study has been carried out in two stages. Both of them based on computational fluid dynamics (CFD) coupled with Lagrangian particle tracking method. The first stage of the work evaluates a variety of strut thicknesses and inter-strut spacings, contrasting with the device-free baseline geometry. The analysis is carried out by imposing flowrate waveforms characteristic of both healthy and AF patients. Boundary conditions are calibrated to reproduce physiological flowrates and pressures in a patient's aortic arch. In the second stage, the optimal geometric design from the first stage was employed, with the addition of lateral struts to prevent the filtration of particles and electronegatively charged strut surfaces, studying the effect of electrical forces on the clots if they are considered charged. Flowrate boundary conditions were used to emulate both healthy and AF conditions. Results from numerical simulations coming form the first stage indicate that the device blocks particles of sizes larger than the inter-strut spacing. It was found that lateral strut space had the highest impact on efficacy. Based on the results of the second stage, deploying the electronegatively charged device in all three aortic arch arteries, the number of particles entering these arteries was reduced on average by 62.6% and 51.2%, for the healthy and diseased models respectively, matching or surpassing current oral anticoagulant efficacy. In conclusion, the device demonstrated a two-fold mechanism for filtering emboli: while the smallest particles are deflected by electrostatic repulsion, avoiding microembolisms, which could lead to cognitive impairment, the largest ones are mechanically filtered since they cannot fit in between the struts, effectively blocking the full range of particle sizes analyzed in this study. The device presented in this manuscript offers an anticoagulant-free method to prevent stroke and SBIs, imperative given the growing population of AF and elderly patients.

Ventricular anatomical complexity and sex differences impact predictions from electrophysiological computational models.

The aim of this work was to analyze the influence of sex hormones and anatomical details (trabeculations and false tendons) on the electrophysiology of healthy human hearts. Additionally, sex- and anatomy-dependent effects of ventricular tachycardia (VT) inducibility are presented. To this end, four anatomically normal, human, biventricular geometries (two male, two female), with identifiable trabeculations, were obtained from high-resolution, ex-vivo MRI and represented by detailed and smoothed geometrical models (with and without the trabeculations). Additionally one model was augmented by a scar. The electrophysiology finite element model (FEM) simulations were carried out, using O'Hara-Rudy human myocyte model with sex phenotypes of Yang and Clancy. A systematic comparison between detailed vs smooth anatomies, male vs female normal hearts was carried out. The heart with a myocardial infarction was subjected to a programmed stimulus protocol to identify the effects of sex and anatomical detail on ventricular tachycardia inducibility. All female hearts presented QT-interval prolongation however the prolongation interval in comparison to the male phenotypes was anatomy-dependent and was not correlated to the size of the heart. Detailed geometries showed QRS fractionation and increased T-wave magnitude in comparison to the corresponding smoothed geometries. A variety of sustained VTs were obtained in the detailed and smoothed male geometries at different pacing locations, which provide evidence of the geometry-dependent differences regarding the prediction of the locations of reentry channels. In the female phenotype, sustained VTs were induced in both detailed and smooth geometries with RV apex pacing, however no consistent reentry channels were identified. Anatomical and physiological cardiac features play an important role defining risk in cardiac disease. These are often excluded from cardiac electrophysiology simulations. The assumption that the cardiac endocardium is smooth may produce inaccurate predictions towards the location of reentry channels in in-silico tachycardia inducibility studies.

Fluid-structure interaction analysis of eccentricity and leaflet rigidity on thrombosis biomarkers in bioprosthetic aortic valve replacements.

This work intends to study the effect of aortic annulus eccentricity and leaflet rigidity on the performance, thrombogenic risk and calcification risk in bioprosthetic aortic valve replacements (BAVRs). To address these questions, a two-way immersed fluid-structure interaction (FSI) computational model was implemented in a high-performance computing (HPC) multi-physics simulation software, and validated against a well-known FSI benchmark. The aortic valve bioprosthesis model is qualitatively contrasted against experimental data, showing good agreement in closed and open states. Regarding the performance of BAVRs, the model predicts that increasing eccentricities yield lower geometric orifice areas (GOAs) and higher normalized transvalvular pressure gradients (TPGs) for healthy cardiac outputs during systole, agreeing with in vitro experiments. Regions with peak values of residence time are observed to grow with eccentricity in the sinus of Valsalva, indicating an elevated risk of thrombus formation for eccentric configurations. In addition, the computational model is used to analyze the effect of varying leaflet rigidity on both performance, thrombogenic and calcification risks with applications to tissue-engineered prostheses. For more rigid leaflets it predicts an increase in systolic and diastolic TPGs, and decrease in systolic GOA, which translates to decreased valve performance. The peak shear rate and residence time regions increase with leaflet rigidity, but their volume-averaged values were not significantly affected. Peak solid stresses are also analyzed, and observed to increase with rigidity, elevating risk of valve calcification and structural failure. To the authors' knowledge this is the first computational FSI model to study the effect of eccentricity or leaflet rigidity on thrombogenic biomarkers, providing a novel tool to aid device manufacturers and clinical practitioners.

Design and execution of a verification, validation, and uncertainty quantification plan for a numerical model of left ventricular flow after LVAD implantation.

BACKGROUND: Left ventricular assist devices (LVADs) are implantable pumps that act as a life support therapy for patients with severe heart failure. Despite improving the survival rate, LVAD therapy can carry major complications. Particularly, the flow distortion introduced by the LVAD in the left ventricle (LV) may induce thrombus formation. While previous works have used numerical models to study the impact of multiple variables in the intra-LV stagnation regions, a comprehensive validation analysis has never been executed. The main goal of this work is to present a model of the LV-LVAD system and to design and follow a verification, validation and uncertainty quantification (VVUQ) plan based on the ASME V&V40 and V&V20 standards to ensure credible predictions. METHODS: The experiment used to validate the simulation is the SDSU cardiac simulator, a bench mock-up of the cardiovascular system that allows mimicking multiple operation conditions for the heart-LVAD system. The numerical model is based on Alya, the BSC's in-house platform for numerical modelling. Alya solves the Navier-Stokes equation with an Arbitrary Lagrangian-Eulerian (ALE) formulation in a deformable ventricle and includes pressure-driven valves, a 0D Windkessel model for the arterial output and a LVAD boundary condition modeled through a dynamic pressure-flow performance curve. The designed VVUQ plan involves: (a) a risk analysis and the associated credibility goals; (b) a verification stage to ensure correctness in the numerical solution procedure; (c) a sensitivity analysis to quantify the impact of the inputs on the four quantities of interest (QoIs) (average aortic root flow [Formula: see text], maximum aortic root flow [Formula: see text], average LVAD flow [Formula: see text], and maximum LVAD flow [Formula: see text]); (d) an uncertainty quantification using six validation experiments that include extreme operating conditions. RESULTS: Numerical code verification tests ensured correctness of the solution procedure and numerical calculation verification showed a grid convergence index (GCI)95% <3.3%. The total Sobol indices obtained during the sensitivity analysis demonstrated that the ejection fraction, the heart rate, and the pump performance curve coefficients are the most impactful inputs for the analysed QoIs. The Minkowski norm is used as validation metric for the uncertainty quantification. It shows that the midpoint cases have more accurate results when compared to the extreme cases. The total computational cost of the simulations was above 100 [core-years] executed in around three weeks time span in Marenostrum IV supercomputer. CONCLUSIONS: This work details a novel numerical model for the LV-LVAD system, that is supported by the design and execution of a VVUQ plan created following recognised international standards. We present a methodology demonstrating that stringent VVUQ according to ASME standards is feasible but computationally expensive.

Concomitant Respiratory Failure Can Impair Myocardial Oxygenation in Patients with Acute Cardiogenic Shock Supported by VA-ECMO.

Venous-arterial extracorporeal membrane oxygenation (VA-ECMO) treatment for acute cardiogenic shock in patients who also have acute lung injury predisposes development of a serious complication called "north-south syndrome" (NSS) which causes cerebral hypoxia. NSS is poorly characterized and hemodynamic studies have focused on cerebral perfusion ignoring the heart. We hypothesized in NSS the heart would be more likely to receive hypoxemic blood than the brain due to the proximity of the coronary arteries to the aortic annulus. To test this, we conducted a computational fluid dynamics simulation of blood flow in a human supported by VA-ECMO. Simulations quantified the fraction of blood at each aortic branching vessel originating from residual native cardiac output versus VA-ECMO. As residual cardiac function was increased, simulations demonstrated myocardial hypoxia would develop prior to cerebral hypoxia. These results illustrate the conditions where NSS will develop and the relative cardiac function that will lead to organ-specific hypoxia. Illustration of the impact of north-south syndrome on organ-specific oxygen delivery. Patients on VA-ECMO have two sources of blood flow, one from the VA-ECMO circuit and one from the residual cardiac function. When there is no residual cardiac function, all organs are perfused with oxygenated blood. As myocardial recovery progresses, blood supply from the two sources will begin to mix resulting in non-homogeneous mixing and differential oxygenation based upon the anatomical site of branching vessels.

Exercise Capacity in Young Adults Born Small for Gestational Age.

Importance: Being born small for gestational age (SGA), approximately 10% of all births, is associated with increased risk of cardiovascular mortality in adulthood, but mechanistic pathways are unclear. Cardiac remodeling and dysfunction occur in fetuses SGA and children born SGA, but it is uncertain whether and how these changes persist into adulthood. Objective: To evaluate baseline cardiac function and structure and exercise capacity in young adults born SGA. Design, Setting, and Participants: This cohort study conducted from January 2015 to January 2018 assessed a perinatal cohort born at a tertiary university hospital in Spain between 1975 and 1995. Participants included 158 randomly selected young adults aged 20 to 40 years born SGA (birth weight below the 10th centile) or with intrauterine growth within standard reference ranges (controls). Participants provided their medical history, filled out questionnaires regarding smoking and physical activity habits, and underwent incremental cardiopulmonary exercise stress testing, cardiac magnetic resonance imaging, and a physical examination, with blood pressure, glucose level, and lipid profile data collected. Exposure: Being born SGA. Main Outcomes and Measures: Cardiac structure and function assessed by cardiac magnetic resonance imaging, including biventricular end-diastolic shape analysis. Exercise capacity assessed by incremental exercise stress testing. Results: This cohort study included 81 adults born SGA (median age at study, 34.4 years [IQR, 30.8-36.7 years]; 43 women [53%]) and 77 control participants (median age at study, 33.7 years [interquartile range (IQR), 31.0-37.1 years]; 33 women [43%]). All participants were of White race/ethnicity and underwent imaging, whereas 127 participants (80% of the cohort; 66 control participants and 61 adults born SGA) completed the exercise test. Cardiac shape analysis showed minor changes at rest in right ventricular geometry (DeLong test z, 2.2098; P = .02) with preserved cardiac function in individuals born SGA. However, compared with controls, adults born SGA had lower exercise capacity, with decreased maximal workload (mean [SD], 180 [62] W vs 214 [60] W; P = .006) and oxygen consumption (median, 26.0 mL/min/kg [IQR, 21.5-33.5 mL/min/kg vs 29.5 mL/min/kg [IQR, 24.0-36.0 mL/min/kg]; P = .02). Exercise capacity was significantly correlated with left ventricular mass (ρ = 0.7934; P < .001). Conclusions and Relevance: This cohort of young adults born SGA had markedly reduced exercise capacity. These results support further research to clarify the causes of impaired exercise capacity and the potential association with increased cardiovascular mortality among adults born SGA.

Handling confounding variables in statistical shape analysis - application to cardiac remodelling.

Statistical shape analysis is a powerful tool to assess organ morphologies and find shape changes associated to a particular disease. However, imbalance in confounding factors, such as demographics might invalidate the analysis if not taken into consideration. Despite the methodological advances in the field, providing new methods that are able to capture complex and regional shape differences, the relationship between non-imaging information and shape variability has been overlooked. We present a linear statistical shape analysis framework that finds shape differences unassociated to a controlled set of confounding variables. It includes two confounding correction methods: confounding deflation and adjustment. We applied our framework to a cardiac magnetic resonance imaging dataset, consisting of the cardiac ventricles of 89 triathletes and 77 controls, to identify cardiac remodelling due to the practice of endurance exercise. To test robustness to confounders, subsets of this dataset were generated by randomly removing controls with low body mass index, thus introducing imbalance. The analysis of the whole dataset indicates an increase of ventricular volumes and myocardial mass in athletes, which is consistent with the clinical literature. However, when confounders are not taken into consideration no increase of myocardial mass is found. Using the downsampled datasets, we find that confounder adjustment methods are needed to find the real remodelling patterns in imbalanced datasets.

Fast Quasi-Conformal Regional Flattening of the Left Atrium.

Two-dimensional representation of 3D anatomical structures is a simple and intuitive way for analysing patient information across populations and image modalities. While cardiac ventricles, especially the left ventricle, have an established standard representation (bull's eye plot), the 2D depiction of the left atrium (LA) remains challenging due to its sub-structural complexity including the pulmonary veins (PV) and the left atrial appendage (LAA). Quasi-conformal flattening techniques, successfully applied to cardiac ventricles, require additional constraints in the case of the LA to place the PV and LAA in the same geometrical 2D location for different cases. Some registration-based methods have been proposed but surface registration is time-consuming and prone to errors when the geometries are very different. We propose a novel atrial flattening methodology where a 2D standardised map of the LA is obtained quickly and without errors related to registration. The LA is divided into five regions which are then mapped to their analogue two-dimensional regions. 67 human left atria from magnetic resonance images (MRI) were studied to derive a population-based template representing the averaged relative locations of the PVs and LAA. The clinical application of our methodology is illustrated on different use cases including the integration of MRI and electroanatomical data.

Reproducibility and accuracy of late gadolinium enhancement cardiac magnetic resonance measurements for the detection of left atrial fibrosis in patients undergoing atrial fibrillation ablation procedures.

AIMS: Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) may define left atrial (LA) anatomy and structural remodelling, and facilitate atrial fibrillation (AF) ablation. We aimed to assess the intra- and inter-observer reproducibility and agreement of LGE-CMR parameters with direct application to AF ablation techniques. METHODS AND RESULTS: One experienced and one non-experienced observer performed complete LGE-CMR data analysis twice, on different days, in 40 randomly selected LGE-CMR examinations [20 performed before ablation (pre-ablation) and 20 performed 3 months after ablation (post-ablation)]. Four additional observers (two experienced and two non-experienced) performed complete LGE-CMR data analysis in a subgroup of 30 patients (15 pre-ablation and 15 post-ablation). All LGE-CMR were performed in sinus rhythm. Intra- and inter-observer reproducibility of LA volume, LA area, and sphericity index (SI) was high: coefficient of variation <10% and intraclass correlation coefficient >0.71. Geometric congruency of repeated reconstruction of LA shape was high: maximal error <5 mm for intra-observer and <8 mm for inter-observer. The precision of scar location increased with extent of scar, and was high (Dice coefficient >0.75) when the scar area was >5 cm2 for a single observer and >15 cm2 for multiple observers. Non-experienced observers performed equally well to experienced observers. CONCLUSION: Late gadolinium enhancement cardiac magnetic resonance measurements of LA area, volume, and SI were reproducible, and geometric congruency of LA shape was high. Location of scar was precise for scar areas >5 cm2 for single observers and >15 cm2 for multiple observers, regardless of the observers' experience. These results may serve as a reference for future studies on the role for substrate-based AF ablation procedures.

Mind the gap: Quantification of incomplete ablation patterns after pulmonary vein isolation using minimum path search.

Pulmonary vein isolation (PVI) is a common procedure for the treatment of atrial fibrillation (AF) since the initial trigger for AF frequently originates in the pulmonary veins. A successful isolation produces a continuous lesion (scar) completely encircling the veins that stops activation waves from propagating to the atrial body. Unfortunately, the encircling lesion is often incomplete, becoming a combination of scar and gaps of healthy tissue. These gaps are potential causes of AF recurrence, which requires a redo of the isolation procedure. Late-gadolinium enhanced cardiac magnetic resonance (LGE-CMR) is a non-invasive method that may also be used to detect gaps, but it is currently a time-consuming process, prone to high inter-observer variability. In this paper, we present a method to semi-automatically identify and quantify ablation gaps. Gap quantification is performed through minimum path search in a graph where every node is a scar patch and the edges are the geodesic distances between patches. We propose the Relative Gap Measure (RGM) to estimate the percentage of gap around a vein, which is defined as the ratio of the overall gap length and the total length of the path that encircles the vein. Additionally, an advanced version of the RGM has been developed to integrate gap quantification estimates from different scar segmentation techniques into a single figure-of-merit. Population-based statistical and regional analysis of gap distribution was performed using a standardised parcellation of the left atrium. We have evaluated our method on synthetic and clinical data from 50 AF patients who underwent PVI with radiofrequency ablation. The population-based analysis concluded that the left superior PV is more prone to lesion gaps while the left inferior PV tends to have less gaps (p < .05 in both cases), in the processed data. This type of information can be very useful for the optimization and objective assessment of PVI interventions.

Machine learning-based phenogrouping in heart failure to identify responders to cardiac resynchronization therapy.

AIMS: We tested the hypothesis that a machine learning (ML) algorithm utilizing both complex echocardiographic data and clinical parameters could be used to phenogroup a heart failure (HF) cohort and identify patients with beneficial response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: We studied 1106 HF patients from the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) (left ventricular ejection fraction ≤ 30%, QRS ≥ 130 ms, New York Heart Association class ≤ II) randomized to CRT with a defibrillator (CRT-D, n = 677) or an implantable cardioverter defibrillator (ICD, n = 429). An unsupervised ML algorithm (Multiple Kernel Learning and K-means clustering) was used to categorize subjects by similarities in clinical parameters, and left ventricular volume and deformation traces at baseline into mutually exclusive groups. The treatment effect of CRT-D on the primary outcome (all-cause death or HF event) and on volume response was compared among these groups. Our analysis identified four phenogroups, significantly different in the majority of baseline clinical characteristics, biomarker values, measures of left and right ventricular structure and function and the primary outcome occurrence. Two phenogroups included a higher proportion of known clinical characteristics predictive of CRT response, and were associated with a substantially better treatment effect of CRT-D on the primary outcome [hazard ratio (HR) 0.35; 95% confidence interval (CI) 0.19-0.64; P = 0.0005 and HR 0.36; 95% CI 0.19-0.68; P = 0.001] than observed in the other groups (interaction P = 0.02). CONCLUSIONS: Our results serve as a proof-of-concept that, by integrating clinical parameters and full heart cycle imaging data, unsupervised ML can provide a clinically meaningful classification of a phenotypically heterogeneous HF cohort and might aid in optimizing the rate of responders to specific therapies.

Complex Congenital Heart Disease Associated With Disordered Myocardial Architecture in a Midtrimester Human Fetus.

BACKGROUND: In the era of increasingly successful corrective interventions in patients with congenital heart disease (CHD), global and regional myocardial remodeling are emerging as important sources of long-term morbidity/mortality. Changes in organization of the myocardium in CHD, and in its mechanical properties, conduction, and blood supply, result in altered myocardial function both before and after surgery. To gain a better understanding and develop appropriate and individualized treatment strategies, the microscopic organization of cardiomyocytes, and their integration at a macroscopic level, needs to be completely understood. The aim of this study is to describe, for the first time, in 3 dimensions and nondestructively the detailed remodeling of cardiac microstructure present in a human fetal heart with complex CHD. METHODS AND RESULTS: Synchrotron X-ray phase-contrast imaging was used to image an archival midgestation formalin-fixed fetal heart with right isomerism and complex CHD and compare with a control fetal heart. Analysis of myocyte aggregates, at detail not accessible with other techniques, was performed. Macroanatomic and conduction system changes specific to the disease were clearly observable, together with disordered myocyte organization in the morphologically right ventricle myocardium. Electrical activation simulations suggested altered synchronicity of the morphologically right ventricle. CONCLUSIONS: We have shown the potential of X-ray phase-contrast imaging for studying cardiac microstructure in the developing human fetal heart at high resolution providing novel insight while preserving valuable archival material for future study. This is the first study to show myocardial alterations occur in complex CHD as early as midgestation.

Quantification of the detailed cardiac left ventricular trabecular morphogenesis in the mouse embryo.

During embryogenesis, a mammalian heart develops from a simple tubular shape into a complex 4-chamber organ, going through four distinct phases: early primitive tubular heart, emergence of trabeculations, trabecular remodeling and development of the compact myocardium. In this paper we propose a framework for standardized and subject-independent 3D regional myocardial complexity analysis, applied to analysis of the development of the mouse left ventricle. We propose a standardized subdivision of the myocardium into 3D overlapping regions (in our case 361) and a novel visualization of myocardial complexity, whereupon we: 1) extend the fractal dimension, commonly applied to image slices, to 3D and 2) use volume occupied by the trabeculations in each region together with their surface area, in order to quantify myocardial complexity. The latter provides an intuitive characterization of the complexity, given that compact myocardium will tend to occupy a larger volume with little surface area while high surface area with low volume will correspond to highly trabeculated areas. Using 50 mouse embryo images at 5 different gestational ages (10 subjects per gestational age), we demonstrate how the proposed representation and complexity measures describe the development of LV myocardial complexity. The mouse embryo data was acquired using high resolution episcopic microscopy. The complexity analysis per region was carried out using: 3D fractal dimension, myocardial volume, myocardial surface area and ratio between the two. The analysis of gestational ages was performed on embryos of 14.5, 15.5, 16.5, 17.5 and 18.5 embryonic days, and demonstrated that the regional complexity of the trabeculations increases longitudinally from the base to the apex, with a maximum around the middle. The overall complexity decreases with gestational age, being most complex at 14.5. Circumferentially, at ages 14.5, 15.5 and 16.5, the trabeculations show similar complexity everywhere except for the anteroseptal and inferolateral area of the wall, where it is smaller. At 17.5 days, the regions of high complexity become more localized towards the inferoseptal and anterolateral parts of the wall. At 18.5 days, the high complexity area exhibits further localization at the inferoseptal and anterior part of the wall.

Evaluating the roles of detailed endocardial structures on right ventricular haemodynamics by means of CFD simulations.

Computational modelling plays an important role in right ventricular (RV) haemodynamic analysis. However, current approaches use smoothed ventricular anatomies. The aim of this study is to characterise RV haemodynamics including detailed endocardial structures like trabeculae, moderator band, and papillary muscles. Four paired detailed and smoothed RV endocardium models (2 male and 2 female) were reconstructed from ex vivo human hearts high-resolution magnetic resonance images. Detailed models include structures with ≥1 mm2 cross-sectional area. Haemodynamic characterisation was done by computational fluid dynamics simulations with steady and transient inflows, using high-performance computing. The differences between the flows in smoothed and detailed models were assessed using Q-criterion for vorticity quantification, the pressure drop between inlet and outlet, and the wall shear stress. Results demonstrated that detailed endocardial structures increase the degree of intra-ventricular pressure drop, decrease the wall shear stress, and disrupt the dominant vortex creating secondary small vortices. Increasingly turbulent blood flow was observed in the detailed RVs. Female RVs were less trabeculated and presented lower pressure drops than the males. In conclusion, neglecting endocardial structures in RV haemodynamic models may lead to inaccurate conclusions about the pressures, stresses, and blood flow behaviour in the cavity.

Preferential regional distribution of atrial fibrosis in posterior wall around left inferior pulmonary vein as identified by late gadolinium enhancement cardiac magnetic resonance in patients with atrial fibrillation.

Aims: Left atrial (LA) fibrosis can be identified by late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) in patients with atrial fibrillation (AF). However, there is limited information about anatomical fibrosis distribution in the left atrium. The aim is to determine whether there is a preferential spatial distribution of fibrosis in the left atrium in patients with AF. Methods and results: A 3-Tesla LGE-CMR was performed in 113 consecutive patients referred for AF ablation. Images were post-processed and analysed using ADAS-AF software (Galgo Medical), which allows fibrosis identification in 3D colour-coded shells. A regional semiautomatic LA parcellation software was used to divide the atrial wall into 12 segments: 1-4, posterior wall; 5-6, floor; 7, septal wall; 8-11, anterior wall; 12, lateral wall. The presence and amount of fibrosis in each segment was obtained for analysis. After exclusions for artefacts and insufficient image quality, 76 LGE-MRI images (68%) were suitable for fibrosis analysis. Segments 3 and 5, closest to the left inferior pulmonary vein, had significantly higher fibrosis (40.42% ± 23.96 and 25.82% ± 21.24, respectively; P < 0.001), compared with other segments. Segments 8 and 10 in the anterior wall contained the lowest fibrosis (2.54% ± 5.78 and 3.82% ± 11.59, respectively; P < 0.001). Age >60 years was significantly associated with increased LA fibrosis [95% confidence interval (CI) 0.19-8.39, P = 0.04] and persistent AF approached significance (95% CI -0.19% to 7.83%, P = 0.08). Conclusion: In patients with AF, the fibrotic area is preferentially located at the posterior wall and floor around the antrum of the left inferior pulmonary vein. Age >60 years was associated with increased fibrosis.

Sensitivity analysis of geometrical parameters to study haemodynamics and thrombus formation in the left atrial appendage.

The left atrial appendage (LAA) is a complex and heterogeneous protruding structure of the left atrium (LA). In atrial fibrillation patients, it is the location where 90% of the thrombi are formed. However, the role of the LAA in thrombus formation is not fully known yet. The main goal of this work is to perform a sensitivity analysis to identify the most relevant LA and LAA morphological parameters in atrial blood flow dynamics. Simulations were run on synthetic ellipsoidal left atria models where different parameters were individually studied: pulmonary veins and mitral valve dimensions; LAA shape; and LA volume. Our computational analysis confirmed the relation between large LAA ostia, low blood flow velocities and thrombus formation. Additionally, we found that pulmonary vein configuration exerted a critical influence on LAA blood flow patterns. These findings contribute to a better understanding of the LAA and to support clinical decisions for atrial fibrillation patients.

Left Ventricular Trabeculations Decrease the Wall Shear Stress and Increase the Intra-Ventricular Pressure Drop in CFD Simulations.

The aim of the present study is to characterize the hemodynamics of left ventricular (LV) geometries to examine the impact of trabeculae and papillary muscles (PMs) on blood flow using high performance computing (HPC). Five pairs of detailed and smoothed LV endocardium models were reconstructed from high-resolution magnetic resonance images (MRI) of ex-vivo human hearts. The detailed model of one LV pair is characterized only by the PMs and few big trabeculae, to represent state of art level of endocardial detail. The other four detailed models obtained include instead endocardial structures measuring ≥1 mm2 in cross-sectional area. The geometrical characterizations were done using computational fluid dynamics (CFD) simulations with rigid walls and both constant and transient flow inputs on the detailed and smoothed models for comparison. These simulations do not represent a clinical or physiological scenario, but a characterization of the interaction of endocardial structures with blood flow. Steady flow simulations were employed to quantify the pressure drop between the inlet and the outlet of the LVs and the wall shear stress (WSS). Coherent structures were analyzed using the Q-criterion for both constant and transient flow inputs. Our results show that trabeculae and PMs increase the intra-ventricular pressure drop, reduce the WSS and disrupt the dominant single vortex, usually present in the smoothed-endocardium models, generating secondary small vortices. Given that obtaining high resolution anatomical detail is challenging in-vivo, we propose that the effect of trabeculations can be incorporated into smoothed ventricular geometries by adding a porous layer along the LV endocardial wall. Results show that a porous layer of a thickness of 1.2·10-2 m with a porosity of 20 kg/m2 on the smoothed-endocardium ventricle models approximates the pressure drops, vorticities and WSS observed in the detailed models.

The reproducibility of late gadolinium enhancement cardiovascular magnetic resonance imaging of post-ablation atrial scar: a cross-over study.

BACKGROUND: Cardiovascular magnetic resonance (CMR) imaging has been used to visualise post-ablation atrial scar (PAAS), generally employing a three-dimensional (3D) late gadolinium enhancement (LGE) technique. However the reproducibility of PAAS imaging has not been determined. This cross-over study is the first to investigate the reproducibility of the technique, crucial for both future research design and clinical implementation. METHODS: Forty subjects undergoing first time ablation for atrial fibrillation (AF) had detailed CMR assessment of PAAS. Following baseline pre-ablation scan, two scans (separated by 48 h) were performed at three months post-ablation. Each scan session included 3D LGE acquisition at 10, 20 and 30 min post administration of gadolinium-based contrast agent (GBCA). Subjects were allocated at second scan post-ablation to identical imaging parameters ('Repro', n = 10), 3 T scanner ('3 T', n = 10), half-slice thickness ('Half-slice', n = 10) or half GBCA dose ('Half-gad', n = 10). PAAS was compared to baseline scar and then reproducibility was assessed for two measures of thresholded scar (% left atrial (LA) occupied by PAAS (%LA PAAS) and Pulmonary Vein Encirclement (PVE)), and then four measures of non-thresholded scar (point-by-point assessment of PAAS, four normalisation methods). Thresholded measures of PAAS were evaluated against procedural outcome (AF recurrence). RESULTS: A total of 271 3D acquisitions (out of maximum 280, 96.7%) were acquired. At 20 and 30 min, inter-scan reproducibility was good to excellent (coefficient of variation at 20 min and 30 min: %LA PAAS 0.41 and 0.20; PVE 0.13 and 0.04 respectively for 'Repro' group). Changes in imaging parameters, especially reduced GBCA dose, reduced inter-scan reproducibility, but for most measures remained good to excellent (ICC for %LA PAAS 0.454-0.825, PVE 0.618-0.809 at 30 min). For non-thresholded scar, highest reproducibility was observed using blood pool z-score normalisation technique: inter-scan ICC 0.759 (absolute agreement, 'Repro' group). There was no significant relationship between indices of PAAS and AF recurrence. CONCLUSION: PAAS imaging is a reproducible finding. Imaging should be performed at least 20 min post-GBCA injection, and a blood pool z-score should be considered for normalisation of signal intensities. The clinical implications of these findings remain to be established in the absence of a simple correlation with arrhythmia outcome. TRIAL REGISTRATION: United Kingdom National Research Ethics Service 08/H0802/68 - 30th September 2008.

Relationship between the left ventricular size and the amount of trabeculations.

Contemporary imaging modalities offer noninvasive quantification of myocardial deformation; however, they make gross assumptions about internal structure of the cardiac walls. Our aim is to study the possible impact of the trabeculations on the stroke volume, strain, and capacity of differently sized ventricles. The cardiac left ventricle is represented by an ellipsoid and the trabeculations by a tissue occupying a fixed volume. The ventricular contraction is modeled by scaling the ellipsoid whereupon the measurements of longitudinal strain, end-diastolic, end-systolic, and stroke volumes are derived and compared. When the trabeculated and nontrabeculated ventricles, having the same geometry and deformation pattern, contain the same amount of blood and contract with the same strain, we observed an increased stroke volume in our model of the trabeculated ventricle. When these ventricles contain and eject the same amount of blood, we observed a reduced strain in the trabeculated case. We identified that a trade-off between the strain and the amount of trabeculations could be reached with a 0.35- to 0.41-cm dense trabeculated layer, without blood filled recesses (for a ventricle with end-diastolic volume of about 150 mL). A trabeculated ventricle can work at lower strains compared to a nontrabeculated ventricle to produce the same stroke volume, which could be a possible explanation why athletes and pregnant women develop reversible signs of left ventricular noncompaction, since the trabeculations could help generating extra cardiac output. This knowledge might help to assess heart failure patients with dilated cardiomyopathies who often show signs of noncompaction.