An open-ended primary-care group intervention for insomnia based on a self-help book - A randomized controlled trial and 4-year follow-up.

Chronic insomnia is a common and burdensome problem for patients seeking primary care. Cognitive behavioural therapy has been shown to be effective for insomnia, also when presented with co-morbidities, but access to sleep therapists is limited. Group-treatment and self-administered treatment via self-help books have both been shown to be efficacious treatment options, and the present study aimed to evaluate the effect of an open-ended group intervention based on a self-help book for insomnia, adapted to fit a primary-care setting. Forty primary-care patients with insomnia (mean age 55 years, 80% women) were randomized to the open-ended group intervention based on a cognitive behavioural therapy for insomnia self-help book or to a care as usual/wait-list control condition. Results show high attendance to group sessions and high treatment satisfaction. Participants in the control group later received the self-help book, but without the group intervention. The book-based group treatment resulted in significantly improved insomnia severity, as well as shorter sleep-onset latency, less wake time after sleep onset, and less use of sleep medication compared with treatment as usual. The improvements were sustained at a 4-year follow-up assessment. A secondary analysis found a significant advantage of the combination of the book and the open-ended group intervention compared with when the initial control group later used only the self-help book. An open-ended treatment group based on a self-help book for insomnia thus seems to be an effective and feasible intervention for chronic insomnia in primary-care settings.

Altered patterns of displacement within the Achilles tendon following surgical repair.

PURPOSE: Ultrasound speckle tracking was used to compare tendon deformation patterns between uninjured and surgically repaired Achilles tendons at 14-27-month follow-up. The hypothesis was that the non-homogenous displacement pattern previously described in uninjured tendons, where displacement within deep layers of the tendons exceeds that of superficial layers, is altered following tendon rupture and subsequent surgical repair. METHODS: In the first part of this study, an in-house-developed block-matching speckle tracking algorithm was evaluated for assessment of displacement on porcine flexor digitorum tendons. Displacement data from speckle tracking were compared to displacement data from manual tracking. In the second part of the study, eleven patients with previous unilateral surgically treated Achilles tendon rupture were investigated using ultrasound speckle tracking. The difference in superficial and deep tendon displacement was assessed. Displacement patterns in the surgically repaired and uninjured tendons were compared during passive motion (Thompson's squeeze test) and during active ankle dorsiflexion. RESULTS: The difference in peak displacement between superficial and deep layers was significantly (p < 0.01) larger in the uninjured tendons as compared to the surgically repaired tendons both during Thompson's test (-0.7 ± 0.2 mm compared to -0.1 ± 0.1 mm) and active dorsiflexion (3.3 ± 1.1 mm compared to 0.3 ± 0.2 mm). The evaluation of the speckle tracking algorithm showed correlations of r ≥ 0.89 between displacement data acquired from speckle tracking and the reference displacement acquired from manual tracking. Speckle tracking systematically underestimated the magnitude of displacement with coefficients of variation of less than 11.7%. CONCLUSIONS: Uninjured Achilles tendons display a non-uniform displacement pattern thought to reflect gliding between fascicles. This pattern was altered after a mean duration of 19 ± 4 months following surgical repair of the tendon indicating that fascicle sliding is impaired. This may affect modulation of the action between different components of the triceps surae, which in turn may affect force transmission and tendon elasticity resulting in impaired function and risk of re-rupture.

High variability in strain estimation errors when using a commercial ultrasound speckle tracking algorithm on tendon tissue.

BACKGROUND: Ultrasound speckle tracking offers a non-invasive way of studying strain in the free Achilles tendon where no anatomical landmarks are available for tracking. This provides new possibilities for studying injury mechanisms during sport activity and the effects of shoes, orthotic devices, and rehabilitation protocols on tendon biomechanics. PURPOSE: To investigate the feasibility of using a commercial ultrasound speckle tracking algorithm for assessing strain in tendon tissue. MATERIAL AND METHODS: A polyvinyl alcohol (PVA) phantom, three porcine tendons, and a human Achilles tendon were mounted in a materials testing machine and loaded to 4% peak strain. Ultrasound long-axis cine-loops of the samples were recorded. Speckle tracking analysis of axial strain was performed using a commercial speckle tracking software. Estimated strain was then compared to reference strain known from the materials testing machine. Two frame rates and two region of interest (ROI) sizes were evaluated. RESULTS: Best agreement between estimated strain and reference strain was found in the PVA phantom (absolute error in peak strain: 0.21 ± 0.08%). The absolute error in peak strain varied between 0.72 ± 0.65% and 10.64 ± 3.40% in the different tendon samples. Strain determined with a frame rate of 39.4 Hz had lower errors than 78.6 Hz as was the case with a 22 mm compared to an 11 mm ROI. CONCLUSION: Errors in peak strain estimation showed high variability between tendon samples and were large in relation to strain levels previously described in the Achilles tendon.

Endocardial border delineation capability of a novel multimodal polymer-shelled contrast agent.

BACKGROUND: A novel polymer-shelled contrast agent (CA) with multimodal and target-specific potential was developed recently. To determine its ultrasonic diagnostic features, we evaluated the endocardial border delineation as visualized in a porcine model and the concomitant effect on physiological variables. METHODS: Three doses of the novel polymer-shelled CA (1.5 ml, 3 ml, and 5 ml [5 × 10(8) microbubbles (MBs)/ml]) and the commercially available CA SonoVue (1.5 ml [2-5 × 10(8) MBs/ml]) were used. Visual evaluations of ultrasound images of the left ventricle were independently performed by three observers who graded each segment in a 6-segment model as either 0 = not visible, 1 = weakly visible, or 2 = visible. Moreover, the duration of clinically useful contrast enhancement and the left ventricular opacification were determined. During anesthesia, oxygen saturation, heart rate, and arterial pressure were sampled every minute and the effect of injection of CA on these physiological variables was evaluated. RESULTS: The highest dose of the polymer-shelled CA gave results comparable to SonoVue. Thus, no significant difference in the overall segment score distribution (2-47-95 vs. 1-39-104), time for clinically sufficient contrast enhancement (20-40 s for both) and left ventricular overall opacification was found. In contrast, when comparing the endocardial border delineation capacity for different regions SonoVue showed significantly higher segment scores for base and mid, except for the mid region when injecting 1.5 ml of the polymer-shelled CA. Neither high nor low doses of the polymer-shelled CA significantly affected the investigated physiological variables. CONCLUSIONS: This study demonstrated that the novel polymer-shelled CA can be used in contrast-enhanced diagnostic imaging without influence on major physiological variables.

Visualization of multimodal polymer-shelled contrast agents using ultrasound contrast sequences: an experimental study in a tissue mimicking flow phantom.

BACKGROUND: A multimodal polymer-shelled contrast agent (CA) with target specific potential was recently developed and tested for its acoustic properties in a single element transducer setup. Since the developed polymeric CA has different chemical composition than the commercially available CAs, there is an interest to study its acoustic response when using clinical ultrasound systems. The aim of this study was therefore to investigate the acoustic response by studying the visualization capability and shadowing effect of three polymer-shelled CAs when using optimized sequences for contrast imaging. METHODS: The acoustic response of three types of the multimodal CA was evaluated in a tissue mimicking flow phantom setup by measuring contrast to tissue ratio (CTR) and acoustic shadowing using five image sequences optimized for contrast imaging. The measurements were performed over a mechanical index (MI) range of 0.2-1.2 at three CA concentrations (106, 105, 104 microbubbles/ml). RESULTS: The CTR-values were found to vary with the applied contrast sequence, MI and CA. The highest CTR-values were obtained when a contrast sequence optimized for higher MI imaging was used. At a CA concentration of 106 microbubbles/ml, acoustic shadowing was observed for all contrast sequences and CAs. CONCLUSIONS: The CAs showed the potential to enhance ultrasound images generated by available contrast sequences. A CA concentration of 106 MBs/ml implies a non-linear relation between MB concentration and image intensity.

Safety of arterial shear wave elastography-ex-vivoassessment of induced strain and strain rates.

Shear wave elastography (SWE) is a promising technique for characterizing carotid plaques and assessing local arterial stiffness. The mechanical stress to which the tissue is subjected during SWE using acoustic radiation force (ARF), leading to strain at a certain strain rate, is still relatively unknown. Because SWE is increasingly used for arterial applications where the mechanical stress could potentially lead to significant consequences, it is important to understand the risks of SWE-induced strain and strain rate. The aim of this study was to investigate the safety of SWE in terms of induced arterial strain and strain rateex-vivoand in a human carotid arteryin-vivo. SWE was performed on six porcine aortae as a model of the human carotid artery using different combinations of ARF push parameters (push voltage: 60/90 V, aperture width: f/1.0/1.5, push length: 100/150/200µs) and distance to push position. The largest induced strain and strain rate were 1.46% and 54 s-1(90 V, f/1.0, 200µs), respectively. Moreover, the SWE-induced strains and strain rates increased with increasing push voltage, aperture, push length, and decreasing distance between the region of interest and the push. In the human carotid artery, the SWE-induced maximum strain was 0.06% and the maximum strain rate was 1.58 s-1, compared with the maximum absolute strain and strain rate of 12.61% and 5.12 s-1, respectively, induced by blood pressure variations in the cardiac cycle. Our results indicate thatex-vivoarterial SWE does not expose the artery to higher strain rate than normal blood pressure variations, and to strain one order of magnitude higher than normal blood pressure variations, at the push settings and distances from the region of interest used in this study.

Effects of hemodialysis on the cardiovascular system: quantitative analysis using wave intensity wall analysis and tissue velocity imaging.

Cardiovascular disease is the leading cause of death in patients with end-stage renal disease (ESRD). The aim of this study was to investigate the changes in cardiovascular function induced by a single session of hemodialysis (HD) by the analysis of cardiovascular dynamics using wave intensity wall analysis (WIWA) and of systolic and diastolic myocardial function using tissue velocity imaging (TVI). Gray-scale cine loops of the left common carotid artery, conventional echocardiography, and TVI images of the left ventricle were acquired before and after HD in 45 patients (17 women, mean age 54 years) with ESRD. The WIWA indexes, W(1) and preload-adjusted W(1), W(2) and preload-adjusted W(2), and the TVI variables, isovolumic contraction velocity (IVCV), isovolumic contraction time (IVCT), peak systolic velocity (PSV), displacement, isovolumic relaxation velocity (IVRV), isovolumic relaxation time (IVRT), peak early diastolic velocity (E'), and peak late diastolic velocity (A'), were compared before and after HD. The WIWA measurements showed significant increases in W(1) (P < 0.05) and preload-adjusted W(1) (P < 0.01) after HD. W(2) was significantly decreased (P < 0.05) after HD, whereas the change in preload-adjusted W(2) was not significant. Systolic velocities, IVCV (P < 0.001) and PSV (P < 0.01), were increased after HD, whereas the AV-plane displacement was decreased (P < 0.01). For the measured diastolic variables, E' was significantly decreased (P < 0.01) and IVRT was significantly prolonged (P < 0.05), after HD. A few correlations were found between WIWA and TVI variables. The WIWA and TVI measurements indicate that a single session of HD improves systolic function. The load dependency of the diastolic variables seems to be more pronounced than for the systolic variables. Preload-adjusted wave intensity indexes may contribute in the assessment of true LV contractility and relaxation.

Osteoprotegerin is a marker of cardiovascular mortality in patients with chronic kidney disease stages 3-5.

Cardiovascular disease (CVD) is the leading cause of death in patients with chronic kidney disease (CKD). Osteoprotegerin (OPG), known to regulate bone mass by inhibiting osteoclast differentiation and activation, might also play a role in vascular calcification. Increased circulating OPG levels in patients with CKD are associated with aortic calcification and increased mortality. We assessed the predictive role of OPG for all-cause and cardiovascular mortality in patients with CKD stages 3-5 over a 5-year follow-up period. We evaluated the relationship between OPG and all-cause and cardiovascular mortality in 145 CKD patients (stages 3-5) in a prospective observational follow-up study. Inflammation markers, including high-sensitivity C-reactive protein, standard echocardiography, and estimation of intima-media thickness in the common carotid artery, were assessed at baseline, and correlations with OPG levels were determined. The cutoff values for OPG were defined using ROC curves for cardiovascular mortality. Survival was assessed during follow up lasting for up to 5.5 years using Fine and Gray model. A total of 145 (89 men; age 58.9 ± 15.0 years) were followed up. The cutoff value for OPG determined using ROC was 10 pmol/L for general causes mortality and 10.08 pmol/L for CV causes mortality. Patients with higher serum OPG levels presented with higher mortality rates compared to patients with lower levels. Aalen-Johansen cumulative incidence curve analysis demonstrated significantly worse survival rates in individuals with higher baseline OPG levels for all-cause and cardiovascular mortality (p < 0.001). In multivariate analysis, OPG was a marker of general and cardiovascular mortality independent of sex, age, CVD, diabetes, and CRP levels. When CKD stages were included in the multivariate analysis, OPG was an independent marker of all-cause mortality but not cardiovascular mortality. Elevated serum OPG levels were associated with higher all-cause and cardiovascular mortality risk, independent of age, CVD, diabetes, and inflammatory markers, in patients with CKD.

Author Correction: Combined spatiotemporal and frequency-dependent shear wave elastography enables detection of vulnerable carotid plaques as validated by MRI.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Combined spatiotemporal and frequency-dependent shear wave elastography enables detection of vulnerable carotid plaques as validated by MRI.

Fatal cerebrovascular events are often caused by rupture of atherosclerotic plaques. However, rupture-prone plaques are often distinguished by their internal composition rather than degree of luminal narrowing, and conventional imaging techniques might thus fail to detect such culprit lesions. In this feasibility study, we investigate the potential of ultrasound shear wave elastography (SWE) to detect vulnerable carotid plaques, evaluating group velocity and frequency-dependent phase velocities as novel biomarkers for plaque vulnerability. In total, 27 carotid plaques from 20 patients were scanned by ultrasound SWE and magnetic resonance imaging (MRI). SWE output was quantified as group velocity and frequency-dependent phase velocities, respectively, with results correlated to intraplaque constituents identified by MRI. Overall, vulnerable lesions graded as American Heart Association (AHA) type VI showed significantly higher group and phase velocity compared to any other AHA type. A selection of correlations with intraplaque components could also be identified with group and phase velocity (lipid-rich necrotic core content, fibrous cap structure, intraplaque hemorrhage), complementing the clinical lesion classification. In conclusion, we demonstrate the ability to detect vulnerable carotid plaques using combined SWE, with group velocity and frequency-dependent phase velocity providing potentially complementary information on plaque characteristics. With such, the method represents a promising non-invasive approach for refined atherosclerotic risk prediction.

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, νWERP, 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: νWERP-t. We present a theoretical method derivation based on flow covariance, quantifying the impact of flow fluctuations on relative pressure. νWERP-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 patient-specific in-silico model of an acute aortic dissection. Over all tests νWERP-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 νWERP allowing for assessment of relative pressure into previously inaccessible vasculatures, the extended νWERP-t further enlarges the method's clinical scope, underlining its potential as a novel tool for assessing relative pressure in-vivo.

Wave intensity wall analysis: a novel noninvasive method to measure wave intensity.

Wave intensity analysis is a concept providing information about the interaction of the heart and the vascular system. Originally, the technique was invasive. Since then new noninvasive methods have been developed. A recently developed ultrasound technique to estimate tissue motion and deformation is speckle-tracking echocardiography. Speckle tracking-based techniques allow for accurate measurement of movement and deformation variables in the arterial wall in both the radial and the longitudinal direction. The aim of this study was to test if speckle tracking-derived deformation data could be used as input for wave intensity calculations. The new concept was to approximate changes of flow and pressure by deformation changes of the arterial wall in longitudinal and radial directions. Flow changes (dU/dt) were approximated by strain rate (sr, 1/s) of the arterial wall in the longitudinal direction, whereas pressure changes (dP/dt) were approximated by sign reversed strain rate (1/s) in the arterial wall in the radial direction. To validate the new concept, a comparison between the newly developed Wave Intensity Wall Analysis (WIWA) algorithm and a commonly used and validated wave intensity system (SSD-5500, Aloka, Tokyo, Japan) was performed. The studied population consisted of ten healthy individuals (three women, seven men) and ten patients (all men) with coronary artery disease. The present validation study indicates that the mechanical properties of the arterial wall, as measured by a speckle tracking-based technique are a possible input for wave intensity calculations. The study demonstrates good visual agreement between the two systems and the time interval between the two positive peaks (W1-W2) measured by the Aloka system and the WIWA system correlated for the total group (r = 0.595, P < 0.001). The correlation for the diseased subgroup was r = 0.797, P < 0.001 and for the healthy subgroup no significant correlation was found (P > 0.05). The results of the study indicate that the mechanical properties of the arterial wall could be used as input for wave intensity calculations. The WIWA concept is a promising new method that potentially provides several advantages over earlier wave intensity methods, but it still has limitations and needs further refinement and larger studies to find the optimal clinical use.

State diagrams of the heart--a new approach to describing cardiac mechanics.

BACKGROUND: Cardiac time intervals have been described as a measure of cardiac performance, where prolongation, shortening and delay of the different time intervals have been evaluated as markers of cardiac dysfunction. A relatively recently developed method with improved ability to measure cardiac events is Tissue Doppler Imaging (TDI), allowing accurate measurement of myocardial movements. METHODS: We propose the state diagram of the heart as a new visualization tool for cardiac time intervals, presenting comparative, normalized data of systolic and diastolic performance, providing a more complete overview of cardiac function. This study aimed to test the feasibility of the state diagram method by presenting examples demonstrating its potential use in the clinical setting and by performing a clinical study, which included a comparison of the state diagram method with established echocardiography methods (E/E' ratio, LVEF and WMSI). The population in the clinical study consisted of seven patients with non ST-elevation myocardial infarction (NSTEMI) and seven control subjects, individually matched according to age and gender. The state diagram of the heart was generated from TDI curves from seven positions in the myocardium, visualizing the inter- and intraventricular function of the heart by displaying the cardiac phases. RESULTS: The clinical examples demonstrated that the state diagram allows for an intuitive visualization of pathological patterns as ischemia and dyssynchrony. Further, significant differences in percentage duration between the control group and the NSTEMI group were found in eight of the totally twenty phases (10 phases for each ventricle), e.g. in the transition phases (Pre-Ejection and Post-Ejection). These phases were significantly longer (> 2.18%) for the NSTEMI group than for the control group (p < 0.05). No significant differences between the groups were found for the established echocardiography methods. CONCLUSION: The test results clearly indicate that the state diagram has potential to be an efficient tool for visualization of cardiac dysfunction and for detection of NSTEMI.

Estimation of Cardiovascular Relative Pressure Using Virtual Work-Energy.

Many cardiovascular diseases lead to local increases in relative pressure, reflecting the higher costs of driving blood flow. The utility of this biomarker for stratifying the severity of disease has thus driven the development of methods to measure these relative pressures. While intravascular catheterisation remains the most direct measure, its invasiveness limits clinical application in many instances. Non-invasive Doppler ultrasound estimates have partially addressed this gap; however only provide relative pressure estimates for a range of constricted cardiovascular conditions. Here we introduce a non-invasive method that enables arbitrary interrogation of relative pressures throughout an imaged vascular structure, leveraging modern phase contrast magnetic resonance imaging, the virtual work-energy equations, and a virtual field to provide robust and accurate estimates. The versatility and accuracy of the method is verified in a set of complex patient-specific cardiovascular models, where relative pressures into previously inaccessible flow regions are assessed. The method is further validated within a cohort of congenital heart disease patients, providing a novel tool for probing relative pressures in-vivo.

Fixation identification in centroid versus start-point modes using eye-tracking data.

Fixation-identification algorithms, needed for analyses of eye movements, may typically be separated into three categories, viz. (i) velocity-based algorithms, (ii) area-based algorithms, and (iii) dispersion-based algorithms. Dispersion-based algorithms are commonly used but this application introduces some difficulties, one being optimization. Basically, there are two modes to reach this goal of optimization, viz., the start-point mode and the centroid mode. The aim of the present study was to compare and evaluate these two dispersion-based algorithms. Manual inspections were made of 1,400 fixations in each mode. Odds ratios showed that by using the centroid mode for fixation detection, a valid fixation is 2.86 times more likely to be identified than by using the start-point mode. Moreover, the algorithm based on centroid mode dispersion showed a good interpretation speed, accuracy, robustness, and ease of implementation, as well as adequate parameter settings.

Circumferential strain by velocity vector imaging and speckle-tracking echocardiography: validation against sonomicrometry in an aortic phantom.

BACKGROUND: Evaluation of arterial deformation and mechanics using strain analysis on ultrasound greyscale images has gained increasing scientific interest. The aim of this study was to validate in vitro measurements of circumferential strain by velocity vector imaging (VVI) and speckle-tracking echocardiography (STE) against sonomicrometry as a reference method. METHOD: Two polyvinyl alcohol phantoms sized to mimic the descending aorta were constructed and connected to a pulsatile flow pump to obtain high-resistance flow profiles. The ultrasound images of the phantom used for strain analyses were acquired with a transesophageal probe. Global and regional circumferential strains were estimated using VVI and STE and were compared with the strain acquired by sonomicrometry. RESULTS: Global circumferential peak strain estimated by VVI and STE correlated well to sonomicrometry (r = 0·90, P≤0·001; and r = 0·97, P≤0·01) with a systematic bias of -0·78% and +0·63%, respectively. The reference strain levels were 1·07-2·54%. Circumferential strain values obtained by VVI were significantly lower than those obtained by STE (bias -1·41%, P≤0·001). CONCLUSION: Global circumferential strain measured by VVI and STE correlates well with sonomicrometry. However, strain values obtained by VVI and STE differ significantly, which should be taken into consideration when comparing results from studies using different software for aortic strain measurements.

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 <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.

Method comparison for cardiac image registration of coronary computed tomography angiography and 3-D echocardiography.

Treatment decision for coronary artery disease (CAD) is based on both morphological and functional information. Image fusion of coronary computed tomography angiography (CCTA) and three-dimensional echocardiography (3DE) could combine morphology and function into a single image to facilitate diagnosis. Three semiautomatic feature-based methods for CCTA/3DE registration were implemented and applied on CAD patients. Methods were verified and compared using landmarks manually identified by a cardiologist. All methods were found feasible for CCTA/3DE fusion.

Comparison of in vivo vs. ex situ obtained material properties of sheep common carotid artery.

Patient-specific biomechanical modelling can improve preoperative surgical planning. This requires patient-specific geometry as well as patient-specific material properties as input. The latter are, however, still quite challenging to estimate in vivo. This study focuses on the estimation of the mechanical properties of the arterial wall. Firstly, in vivo pressure, diameter and thickness of the arterial wall were acquired for sheep common carotid arteries. Next, the animals were sacrificed and the tissue was stored for mechanical testing. Planar biaxial tests were performed to obtain experimental stress-stretch curves. Finally, parameters for the hyperelastic Mooney-Rivlin and Gasser-Ogden-Holzapfel (GOH) material model were estimated based on the in vivo obtained pressure-diameter data as well as on the ex situ experimental stress-stretch curves. Both material models were able to capture the in vivo behaviour of the tissue. However, in the ex situ case only the GOH model provided satisfactory results. When comparing different fitting approaches, in vivo vs. ex situ, each of them showed its own advantages and disadvantages. The in vivo approach estimates the properties of the tissue in its physiological state while the ex situ approach allows to apply different loadings to properly capture the anisotropy of the tissue. Both of them could be further enhanced by improving the estimation of the stress-free state, i.e. by adding residual circumferential stresses in vivo and by accounting for the flattening effect of the tested samples ex vivo. • Competing interests: none declared • Word count: 4716.

Patient-Specific Left Ventricular Flow Simulations From Transthoracic Echocardiography: Robustness Evaluation and Validation Against Ultrasound Doppler and Magnetic Resonance Imaging.

The combination of medical imaging with computational fluid dynamics (CFD) has enabled the study of 3-D blood flow on a patient-specific level. However, with models based on gated high-resolution data, the study of transient flows, and any model implementation into routine cardiac care, is challenging. This paper presents a novel pathway for patient-specific CFD modelling of the left ventricle (LV), using 4-D transthoracic echocardiography (TTE) as input modality. To evaluate the clinical usability, two sub-studies were performed. First, a robustness evaluation was performed, where repeated models with alternating input variables were generated for six subjects and changes in simulated output quantified. Second, a validation study was carried out, where the pathway accuracy was evaluated against pulsed-wave Doppler (100 subjects), and 2-D through-plane phase-contrast magnetic resonance imaging measurements over seven intraventricular planes (6 subjects). The robustness evaluation indicated a model deviation of <12%, with highest regional and temporal deviations at apical segments and at peak systole, respectively. The validation study showed an error of <11% (velocities <10 cm/s) for all subjects, with no significant regional or temporal differences observed. With the patient-specific pathway shown to provide robust output with high accuracy, and with the pathway dependent only on 4-D TTE, the method has a high potential to be used within future clinical studies on 3-D intraventricular flow patterns. To this, future model developments in the form of e.g., anatomically accurate LV valves may further enhance the clinical value of the simulations.