Modeling Left Atrial Flow, Energy, Blood Heating Distribution in Response to Catheter Ablation Therapy

Introduction: Atrial fibrillation (AF) is a widespread cardiac arrhythmia that commonly affects the left atrium (LA), causing it to quiver instead of contracting effectively. This behavior is triggered by abnormal electrical impulses at a specific site in the atrial wall. Catheter ablation (CA) treatment consists of isolating this driver site by burning the surrounding tissue to restore sinus rhythm (SR). However, evidence suggests that CA can concur to the formation of blood clots by promoting coagulation near the heat source and in regions with low flow velocity and blood stagnation.Methods: A patient-specific modeling workflow was created and applied to simulate thermal-fluid dynamics in two patients pre- and post-CA. Each model was personalized based on pre- and post-CA imaging datasets. The wall motion and anatomy were derived from SSFP Cine MRI data, while the trans-valvular flow was based on Doppler ultrasound data. The temperature distribution in the blood was modeled using a modified Pennes bioheat equation implemented in a finite-element based Navier-Stokes solver. Blood particles were also classified based on their residence time in the LA using a particle-tracking algorithm.Results: SR simulations showed multiple short-lived vortices with an average blood velocity of 0.2-0.22 m/s. In contrast, AF patients presented a slower vortex and stagnant flow in the LA appendage, with the average blood velocity reduced to 0.08–0.14 m/s. Restoration of SR also increased the blood kinetic energy and the viscous dissipation due to the presence of multiple vortices. Particle tracking showed a dramatic decrease in the percentage of blood remaining in the LA for longer than one cycle after CA (65.9 vs. 43.3% in patient A and 62.2 vs. 54.8% in patient B). Maximum temperatures of 76° and 58°C were observed when CA was performed near the appendage and in a pulmonary vein, respectively.Conclusion: This computational study presents novel models to elucidate relations between catheter temperature, patient-specific atrial anatomy and blood velocity, and predict how they change from SR to AF. The models can quantify blood flow in critical regions, including residence times and temperature distribution for different catheter positions, providing a basis for quantifying stroke risks

Generalized super-resolution 4D Flow MRI \unicode{x2013} using ensemble learning to extend across the cardiovascular system

4D Flow Magnetic Resonance Imaging (4D Flow MRI) is a non-invasive measurement technique capable of quantifying blood flow across the cardiovascular system. While practical use is limited by spatial resolution and image noise, incorporation of trained super-resolution (SR) networks has potential to enhance image quality post-scan. However, these efforts have predominantly been restricted to narrowly defined cardiovascular domains, with limited exploration of how SR performance extends across the cardiovascular system; a task aggravated by contrasting hemodynamic conditions apparent across the cardiovasculature. The aim of our study was to explore the generalizability of SR 4D Flow MRI using a combination of heterogeneous training sets and dedicated ensemble learning. With synthetic training data generated across three disparate domains (cardiac, aortic, cerebrovascular), varying convolutional base and ensemble learners were evaluated as a function of domain and architecture, quantifying performance on both in-silico and acquired in-vivo data from the same three domains. Results show that both bagging and stacking ensembling enhance SR performance across domains, accurately predicting high-resolution velocities from low-resolution input data in-silico. Likewise, optimized networks successfully recover native resolution velocities from downsampled in-vivo data, as well as show qualitative potential in generating denoised SR-images from clinical level input data. In conclusion, our work presents a viable approach for generalized SR 4D Flow MRI, with ensemble learning extending utility across various clinical areas of interest.Comment: 10 pages, 5 figure

Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis

Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH. Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting. Methods: Plasma BLVRB levels were measured in patients with symptomatic carotid atherosclerosis from the PARISK study (n = 177, 5 year follow-up) with and without IPH as indicated by MRI. Plasma BLVRB levels were also measured in a mouse vein graft model of IPH at baseline and following antiangiogenic therapy targeting vascular endothelial growth factor receptor 2 (VEGFR-2). Results: Plasma BLVRB levels were significantly higher in patients with IPH (737.32 ± 693.21 vs. 520.94 ± 499.43 mean fluorescent intensity (MFI), p = 0.033), but had no association with baseline clinical and biological parameters. Plasma BLVRB levels were also significantly higher in patients who developed recurrent ischemic stroke (1099.34 ± 928.49 vs. 582.07 ± 545.34 MFI, HR = 1.600, CI [1.092–2.344]; p = 0.016). Plasma BLVRB levels were significantly reduced following prevention of IPH by anti-VEGFR-2 therapy in mouse vein grafts (1189 ± 258.73 vs. 1752 ± 366.84 MFI; p = 0.004). Conclusions: Plasma BLVRB was associated with IPH and increased risk of recurrent ischemic stroke in patients with symptomatic low- to moderate-grade carotid stenosis, indicating the capacity to monitor the efficacy of IPH-preventive pharmacotherapy in an animal model. Together, these results suggest the utility of plasma BLVRB as a biomarker for atherosclerotic plaque instability

Altered Aortic Hemodynamics and Relative Pressure in Patients with Dilated Cardiomyopathy

Abstract Ventricular-vascular interaction is central in the adaptation to cardiovascular disease. However, cardiomyopathy patients are predominantly monitored using cardiac biomarkers. The aim of this study is therefore to explore aortic function in dilated cardiomyopathy (DCM). Fourteen idiopathic DCM patients and 16 controls underwent cardiac magnetic resonance imaging, with aortic relative pressure derived using physics-based image processing and a virtual cohort utilized to assess the impact of cardiovascular properties on aortic behaviour. Subjects with reduced left ventricular systolic function had significantly reduced aortic relative pressure, increased aortic stiffness, and significantly delayed time-to-pressure peak duration. From the virtual cohort, aortic stiffness and aortic volumetric size were identified as key determinants of aortic relative pressure. As such, this study shows how advanced flow imaging and aortic hemodynamic evaluation could provide novel insights into the manifestation of DCM, with signs of both altered aortic structure and function derived in DCM using our proposed imaging protocol. Graphic AbstractrBritish Heart Foundation. New Horizons Program (NH/11/5/29058)Engineering and Physical Sciences Research Council (EP/H046410/1 and EP/N011554/1)Guy's & St. Thomas' NHS Foundation TrustEngineering and Physical Sciences Research Council. Wellcome Trust-EPSRC Centre of Excellence in Medical Engineering ((WT 088641/Z/09/Z)National Institute for Healthcare Research. Cardiovascular MedTech CooperativeMarcus Wallenberg Foundation for International Cooperation in Scienc

Non-invasive imaging for improved cardiovascular diagnostics : Shear wave elastography, relative pressure estimation, and tomographic reconstruction

Throughout the last century, medical imaging has come to revolutionise the way we diagnose disease, and is today an indispensable part of virtually any clinical practice. In cardiovascular care imaging is extensively utilised, and the development of novel techniques promises refined diagnostic abilities: ultrasound elastography allows for constitutive tissue assessment, 4D flow magnetic resonance imaging (MRI) enables full-field flow mapping, and micro-Computed Tomography (CT) permits high-resolution imaging at pre-clinical level. However, following the complex nature of cardiovascular disease, refined methods are still very much needed to accurately utilise these techniques and to effectively isolate disease developments. The aim of this thesis has been to develop such methods for refined cardiovascular image diagnostics. In total eight studies conducted over three separate focus areas have been included: four on vascular shear wave elastography (SWE), three on non-invasive cardiovascular relative pressure estimations, and one on tomographic reconstruction for pre-clinical imaging. In Study I-IV, the accuracy and feasibility of vascular SWE was evaluated, with particular focus on refined carotid plaque characterisation. With confined arterial or plaque tissue restricting acoustic wave propagation, analysis of group and phase velocity was performed with SWE output validated against reference mechanical testing and imaging. The results indicate that geometrical confinement has a significant impact on SWE accuracy, however that a combined group and phase velocity approach can be utilised to identify vulnerable carotid plaque lesions in-vivo. In Study V-VII, a non-invasive method for the interrogation of relative pressure from imaged cardiovascular flow was developed. Using the concept of virtual work-energy, the method was applied to accurately assess relative pressures throughout complex, turbulence-inducing, branching vasculatures. The method was also applied on a dilated cardiomyopathy cohort, indicating arterial hemodynamic changes in cardiac disease. Lastly, in Study VIII a method for multigrid image reconstruction of tomographic data was developed, utilising domain splitting and operator masking to accurately reconstruct high-resolution regions-of-interests at a fraction of the computational cost of conventional full-resolution methods. Together, the eight studies have incorporated a range of different imaging modalities, developed methods for both constitutive and hemodynamic cardiovascular assessment, and utilised refined pre-clinical imaging, all with the same purpose: to refine current state cardiovascular imaging and to improve our ability to non-invasively assess cardiovascular disease. With promising results reached, the studies lay the foundation for continued clinical investigations, advancing the presented methods and maturing their usage for an improved future cardiovascular care.Medicinsk avbildning utgör idag en central del av modern klinisk diagnostik, och bildgivande diagnostikverktyg har kommit att i grunden förändra sättet på vilket dagligt kliniskt arbete utförs. Medicinsk bildteknik används också i stor utsträckning inom hjärt-kärldiagnostik, och i takt med att nya tekniker utvecklas kan förfinad information inhämtas: ultraljudsbaserad elastografi möjliggör avbildning av vävnaders mekaniska egenskaper, fyrdimensionella blodflödesmönster kan kartläggas genom 4D flödes-magnetresonanstomografi (MRI), och mikro-Datortomografi (mikro-CT) möjliggör preklinisk avbildning i mikrometerupplösning. För att kunna dra nytta av dessa teknikers potential i ett kliniskt sammanhang behövs dock förfinade och validerade analysverktyg, särskilt med tanke på hjärt-kärlsjukdomars komplexa och multifaktoriella natur. Syftet med följande avhandling har varit att utveckla sådana metoder för förbättrad hjärt-kärlavbildning. Avhandlingen innehåller totalt åtta delarbeten fördelat över tre fokusområden: fyra inom vaskulär skjuvvågselastografi (SWE), tre inom icke-invasiv tryckfallsmätning, och en inom pre-klinisk tomografisk bildrekonstruktion. I studie I-IV utvärderades vaskulär SWE, med särskilt fokus på teknikens potential för förfinad karaktärisering av karotisplack. I alla studier undersöktes SWE grupp- och fashastighet, med estimerade hastigheter och styvheter validerade mot mekanisk referensmätning eller kompletterande avbildning. Resultaten visar hur spatialt avgränsade kärl eller plack har en tydlig inverkan på SWE:s noggrannhet, men indikerar även hur rupturbenägna plack kan identifieras genom en kombination av grupp- och fashastighetsanalys. I studie V-VII utvecklades en ny metod för icke-invasiv tryckfallsmätning baserad uteslutande på uppmätt 4D-flödesdata. Genom en komplett flödesmekanisk beskrivning i kombination med ett virtuellt flödesfält kan exakta och robusta tryckfallsmätningar genomföras genom komplexa, turbulensinducerande, och kliniskt relevant kardiovaskulära strukturer. Metoden användes också för att analysera en klinisk kohort med dilaterad kardiomyopati, där tydliga förändringar i arteriellt blodtrycksbeteende detekterades. I studie VIII utvecklades en metod för multidimensionell bildrekonstruktion av tomografisk mikro-CT-data. Genom domän- och operatorseparering visar resultaten hur högupplöst rekonstruktion av en subdomän kan uppnås till en bråkdel av den totala tids- eller minnesåtgången som annars fordras för en fullupplöst bildrekonstruktion. Tillsammans har de åtta delstudierna använt ett antal olika avbildningsmodaliteter, applicerat både vävnadsbaserat och hemodynamisk utvärdering av hjärt-kärlsystemet, och slutligen inkluderat preklinisk avbildning, allt för att uppnå samma mål: att förbättra klinisk hjärt-kärlavbildning och ge en fördjupad förståelse av olika hjärt-kärlsjukdomars kliniska manifestation genom icke-invasiv avbildning. Avhandlingen utgör också grunden för fortsatta vetenskapliga studier, där de utvärderade metoderna kan komma att förfinas ytterligare som del av en mer omfattande klinisk implementering.Karolinska Institutet-KTH joint degree doctoral thesis in in medical technology and medical sciences</p

Non-invasive imaging for improved cardiovascular diagnostics : Shear wave elastography, relative pressure estimation, and tomographic reconstruction

Throughout the last century, medical imaging has come to revolutionise the way we diagnose disease, and is today an indispensable part of virtually any clinical practice. In cardiovascular care imaging is extensively utilised, and the development of novel techniques promises refined diagnostic abilities: ultrasound elastography allows for constitutive tissue assessment, 4D flow magnetic resonance imaging (MRI) enables full-field flow mapping, and micro-Computed Tomography (CT) permits high-resolution imaging at pre-clinical level. However, following the complex nature of cardiovascular disease, refined methods are still very much needed to accurately utilise these techniques and to effectively isolate disease developments. The aim of this thesis has been to develop such methods for refined cardiovascular image diagnostics. In total eight studies conducted over three separate focus areas have been included: four on vascular shear wave elastography (SWE), three on non-invasive cardiovascular relative pressure estimations, and one on tomographic reconstruction for pre-clinical imaging. In Study I-IV, the accuracy and feasibility of vascular SWE was evaluated, with particular focus on refined carotid plaque characterisation. With confined arterial or plaque tissue restricting acoustic wave propagation, analysis of group and phase velocity was performed with SWE output validated against reference mechanical testing and imaging. The results indicate that geometrical confinement has a significant impact on SWE accuracy, however that a combined group and phase velocity approach can be utilised to identify vulnerable carotid plaque lesions in-vivo. In Study V-VII, a non-invasive method for the interrogation of relative pressure from imaged cardiovascular flow was developed. Using the concept of virtual work-energy, the method was applied to accurately assess relative pressures throughout complex, turbulence-inducing, branching vasculatures. The method was also applied on a dilated cardiomyopathy cohort, indicating arterial hemodynamic changes in cardiac disease. Lastly, in Study VIII a method for multigrid image reconstruction of tomographic data was developed, utilising domain splitting and operator masking to accurately reconstruct high-resolution regions-of-interests at a fraction of the computational cost of conventional full-resolution methods. Together, the eight studies have incorporated a range of different imaging modalities, developed methods for both constitutive and hemodynamic cardiovascular assessment, and utilised refined pre-clinical imaging, all with the same purpose: to refine current state cardiovascular imaging and to improve our ability to non-invasively assess cardiovascular disease. With promising results reached, the studies lay the foundation for continued clinical investigations, advancing the presented methods and maturing their usage for an improved future cardiovascular care.Medicinsk avbildning utgör idag en central del av modern klinisk diagnostik, och bildgivande diagnostikverktyg har kommit att i grunden förändra sättet på vilket dagligt kliniskt arbete utförs. Medicinsk bildteknik används också i stor utsträckning inom hjärt-kärldiagnostik, och i takt med att nya tekniker utvecklas kan förfinad information inhämtas: ultraljudsbaserad elastografi möjliggör avbildning av vävnaders mekaniska egenskaper, fyrdimensionella blodflödesmönster kan kartläggas genom 4D flödes-magnetresonanstomografi (MRI), och mikro-Datortomografi (mikro-CT) möjliggör preklinisk avbildning i mikrometerupplösning. För att kunna dra nytta av dessa teknikers potential i ett kliniskt sammanhang behövs dock förfinade och validerade analysverktyg, särskilt med tanke på hjärt-kärlsjukdomars komplexa och multifaktoriella natur. Syftet med följande avhandling har varit att utveckla sådana metoder för förbättrad hjärt-kärlavbildning. Avhandlingen innehåller totalt åtta delarbeten fördelat över tre fokusområden: fyra inom vaskulär skjuvvågselastografi (SWE), tre inom icke-invasiv tryckfallsmätning, och en inom pre-klinisk tomografisk bildrekonstruktion. I studie I-IV utvärderades vaskulär SWE, med särskilt fokus på teknikens potential för förfinad karaktärisering av karotisplack. I alla studier undersöktes SWE grupp- och fashastighet, med estimerade hastigheter och styvheter validerade mot mekanisk referensmätning eller kompletterande avbildning. Resultaten visar hur spatialt avgränsade kärl eller plack har en tydlig inverkan på SWE:s noggrannhet, men indikerar även hur rupturbenägna plack kan identifieras genom en kombination av grupp- och fashastighetsanalys. I studie V-VII utvecklades en ny metod för icke-invasiv tryckfallsmätning baserad uteslutande på uppmätt 4D-flödesdata. Genom en komplett flödesmekanisk beskrivning i kombination med ett virtuellt flödesfält kan exakta och robusta tryckfallsmätningar genomföras genom komplexa, turbulensinducerande, och kliniskt relevant kardiovaskulära strukturer. Metoden användes också för att analysera en klinisk kohort med dilaterad kardiomyopati, där tydliga förändringar i arteriellt blodtrycksbeteende detekterades. I studie VIII utvecklades en metod för multidimensionell bildrekonstruktion av tomografisk mikro-CT-data. Genom domän- och operatorseparering visar resultaten hur högupplöst rekonstruktion av en subdomän kan uppnås till en bråkdel av den totala tids- eller minnesåtgången som annars fordras för en fullupplöst bildrekonstruktion. Tillsammans har de åtta delstudierna använt ett antal olika avbildningsmodaliteter, applicerat både vävnadsbaserat och hemodynamisk utvärdering av hjärt-kärlsystemet, och slutligen inkluderat preklinisk avbildning, allt för att uppnå samma mål: att förbättra klinisk hjärt-kärlavbildning och ge en fördjupad förståelse av olika hjärt-kärlsjukdomars kliniska manifestation genom icke-invasiv avbildning. Avhandlingen utgör också grunden för fortsatta vetenskapliga studier, där de utvärderade metoderna kan komma att förfinas ytterligare som del av en mer omfattande klinisk implementering.Karolinska Institutet-KTH joint degree doctoral thesis in in medical technology and medical sciences</p

Data supporting paper - Modelling left atrial flow, energy, blood heating distribution in response to catheter ablation therapy

Two patients pressure, velocity and particle tracking data pre and post catheter ablation therapy. As above submitted to Frontiers

Plaque characterization using shear wave elastography—evaluation of differentiability and accuracy using a combined ex vivo and in vitro setup

Ultrasound elastography has shown potential for improved plaque risk stratification. However, no clear consensus exists on what output metric to use, or what imaging parameters would render optimal plaque differentiation. For this reason we developed a combined ex vivo and in vitro setup, in which the ability to differentiate phantom plaques of varying stiffness was evaluated as a function of plaque geometry, push location, imaging plane, and analysed wave speed metric. The results indicate that group velocity or phase velocity  ⩾1 kHz showed the highest ability to significantly differentiate plaques of different stiffness, successfully classifying a majority of the 24 analysed plaque geometries, respectively. The ability to differentiate plaques was also better in the longitudinal views than in the transverse view. Group velocity as well as phase velocities  &lt;1 kHz showed a systematic underestimation of plaque stiffness, stemming from the confined plaque geometries, however, despite this group velocity analysis showed lowest deviation in estimated plaque stiffness (0.1 m s−1 compared to 0.2 m s−1 for phase velocity analysis). SWE results were also invariant to SWE push location, albeit apparent differences in signal-to-noise ratio (SNR) and generated plaque particle velocity. With that, the study has reinforced the potential of SWE for successful plaque differentiation; however the results also highlight the importance of choosing optimal imaging settings and using an appropriate wave speed metric when attempting to differentiate different plaque groups

Non-invasive estimation of relative pressure in turbulent flow using virtual work-energy

Vascular pressure differences are established risk markers for a number of cardiovascular diseases. Relative pressures are, however, often driven by turbulence-induced flow fluctuations, where conventional non-invasive methods may yield inaccurate results. Recently, we proposed a novel method for non-turbulent flows, nu WERP, utilizing the concept of virtual work-energy to accurately probe relative pressure through complex branching vasculature. Here, we present an extension of this approach for turbulent flows: nu WERP-t. We present a theoretical method derivation based on flow covariance, quantifying the impact of flow fluctuations on relative pressure. nu WERP-t is tested on a set of in-vitro stenotic flow phantoms with data acquired by 4D flow MRI with six-directional flow encoding, as well as on a patientspecific in-silico model of an acute aortic dissection. Over all tests nu WERP-t shows improved accuracy over alternative energy-based approaches, with excellent recovery of estimated relative pressures. In particular, the use of a guaranteed divergence-free virtual field improves accuracy in cases where turbulent flows skew the apparent divergence of the acquired field. With the original nu WERP allowing for assessment of relative pressure into previously inaccessible vasculatures, the extended nu WERP-t further enlarges the methods clinical scope, underlining its potential as a novel tool for assessing relative pressure in-vivo. (C) 2019 The Authors. Published by Elsevier B.V.Funding Agencies|Hans Werthen foundation of the Royal Academy of Engineering Sciences; Galostiftelsen; Erik and Edith Fernstrom Foundation for Medical Research; Basic Science Research Program through the National Research Foundation of Korea (NRF) - Ministry of Education [2018R1D1A1A02043249]; Kangwon National University [D1001679-01-01]; European Unions Horizon 2020 research and Innovation programme under the Marie Sklodowska-Curie grant [764739]; Engineering and Physical Sciences Research CouncilUK Research &amp; Innovation (UKRI)Engineering &amp; Physical Sciences Research Council (EPSRC) [EP/N011554/1, EP/R003866/1]; Wellcome TrustWellcome TrustEuropean Commission [209450/Z/17/Z]; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2018-04454]; Swedish Heart-Lung FoundationSwedish Heart-Lung Foundation [2018-0657]; Wellcome ESPRC Centre for Medical Engineering at Kings College LondonUK Research &amp; Innovation (UKRI)Engineering &amp; Physical Sciences Research Council (EPSRC) [WT 203148/Z/16/Z]; British Heart FoundationBritish Heart Foundation [TG/17/3/33406]</p

Left ventricular outflow obstruction predicts increase in systolic pressure gradients and blood residence time after transcatheter mitral valve replacement

Abstract Left ventricular outflow tract (LVOT) obstruction is a relatively common consequence of transcatheter mitral valve replacement (TMVR). Although LVOT obstruction is associated with heart failure and adverse remodelling, its effects upon left ventricular hemodynamics remain poorly characterised. This study uses validated computational models to identify the LVOT obstruction degree that causes significant changes in ventricular hemodynamics after TMVR. Seven TMVR patients underwent personalised flow simulations based on pre-procedural imaging data. Different virtual valve configurations were simulated in each case, for a total of 32 simulations, and the resulting obstruction degree was correlated with pressure gradients and flow residence times. These simulations identified a threshold LVOT obstruction degree of 35%, beyond which significant deterioration of systolic function was observed. The mean increase from baseline (pre-TMVR) in the peak systolic pressure gradient rose from 5.7% to 30.1% above this threshold value. The average blood volume staying inside the ventricle for more than two cycles also increased from 4.4% to 57.5% for obstruction degrees above 35%, while the flow entering and leaving the ventricle within one cycle decreased by 13.9%. These results demonstrate the unique ability of modelling to predict the hemodynamic consequences of TMVR and to assist in the clinical decision-making process