Circulatory efficiency in patients with severe aortic valve stenosis before and after aortic valve replacement.

BACKGROUND: Circulatory efficiency reflects the ratio between total left ventricular work and the work required for maintaining cardiovascular circulation. The effect of severe aortic valve stenosis (AS) and aortic valve replacement (AVR) on left ventricular/circulatory mechanical power and efficiency is not yet fully understood. We aimed to quantify left ventricular (LV) efficiency in patients with severe AS before and after surgical AVR. METHODS: Circulatory efficiency was computed from cardiovascular magnetic resonance (CMR) imaging derived volumetric data, echocardiographic and clinical data in patients with severe AS (n = 41) before and 4 months after AVR and in age and sex-matched healthy subjects (n = 10). RESULTS: In patients with AS circulatory efficiency was significantly decreased compared to healthy subjects (9 ± 3% vs 12 ± 2%; p = 0.004). There were significant negative correlations between circulatory efficiency and LV myocardial mass (r = - 0.591, p < 0.001), myocardial fibrosis volume (r = - 0.427, p = 0.015), end systolic volume (r = - 0.609, p < 0.001) and NT-proBNP (r = - 0.444, p = 0.009) and significant positive correlation between circulatory efficiency and LV ejection fraction (r = 0.704, p < 0.001). After AVR, circulatory efficiency increased significantly in the total cohort (9 ± 3 vs 13 ± 5%; p < 0.001). However, in 10/41 (24%) patients, circulatory efficiency remained below 10% after AVR and, thus, did not restore to normal values. These patients also showed less reduction in myocardial fibrosis volume compared to patients with restored circulatory efficiency after AVR. CONCLUSION: In our cohort, circulatory efficiency is reduced in patients with severe AS. In 76% of cases, AVR leads to normalization of circulatory efficiency. However, in 24% of patients, circulatory efficiency remained below normal values even after successful AVR. In these patients also less regression of myocardial fibrosis volume was seen. Trial Registration clinicaltrials.gov NCT03172338, June 1, 2017, retrospectively registered.

EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment.

BACKGROUND: Four international study groups undertook a large study in resectable osteosarcoma, which included two randomised controlled trials, to determine the effect on survival of changing post-operative chemotherapy based on histological response. PATIENTS AND METHODS: Patients with resectable osteosarcoma aged ≤40 years were treated with the MAP regimen, comprising pre-operatively of two 5-week cycles of cisplatin 120 mg/m(2), doxorubicin 75 mg/m(2), methotrexate 12 g/m(2) × 2 (MAP) and post-operatively two further cycles of MAP and two cycles of just MA. Patients were randomised after surgery. Those with ≥10% viable tumour in the resected specimen received MAP or MAP with ifosfamide and etoposide. Those with <10% viable tumour were allocated to MAP or MAP followed by pegylated interferon. Longitudinal evaluation of quality of life was undertaken. RESULTS: Recruitment was completed to the largest osteosarcoma study to date in 75 months. Commencing March 2005, 2260 patients were registered from 326 centres across 17 countries. About 1334 of 2260 registered patients (59%) were randomised. Pre-operative chemotherapy was completed according to protocol in 94%. Grade 3-4 neutropenia affected 83% of cycles and 59% were complicated by infection. There were three (0.13%) deaths related to pre-operative chemotherapy. At definitive surgery, 50% of patients had at least 90% necrosis in the resected specimen. CONCLUSIONS: New models of collaboration are required to successfully conduct trials to improve outcomes of patients with rare cancers; EURAMOS-1 demonstrates achievability. Considerable regulatory, financial and operational challenges must be overcome to develop similar studies in the future. The trial is registered as NCT00134030 and ISRCTN 67613327.

Verification Study of in Silico Computed Intracardiac Blood Flow With 4D Flow MRI.

OBJECTIVE: Major challenges for clinical applications of in silico medicine are limitations in time and computational resources. Computational approaches should therefore be tailored to specific applications with relatively low complexity and must be verified and validated against clinical gold standards. METHODS: This study performed computational fluid dynamics simulations of left ventricular hemodynamics of different complexity based on shape reconstruction from steady state gradient echo magnetic resonance imaging (MRI) data. Computed flow results of a rigid wall model (RWM) and a prescribed motion fluid-structure interaction (PM-FSI) model were compared against phase-contrast MRI measurements for three healthy subjects. RESULTS: Extracted boundary conditions from the steady state MRI sequences as well as computed metrics, such as flow rate, valve velocities, and kinetic energy show good agreement with in vivo flow measurements. Regional flow analysis reveals larger differences. CONCLUSION: Basic flow structures are well captured with RWM and PM-FSI. For the computation of further biomarkers like washout or flow efficiency, usage of PM-FSI is required. Regarding boundary-near flow, more accurate anatomical models are inevitable. SIGNIFICANCE: These results delineate areas of application of both methods and lay a foundation for larger validation studies and sensitivity analysis for healthy and diseased cases, being an essential step upon clinical translations.

Osteosarcoma of the mobile spine.

BACKGROUND: The aims of this analysis were to investigate features and outcome of high-grade osteosarcomas of the mobile spine. PATIENTS AND METHODS: Since 1977, 20 Cooperative Osteosarcoma Study Group patients had a diagnosis of high-grade osteosarcomas of the mobile spine and were included in this retrospective analysis of patient-, tumor- and treatment-related variables and outcome. RESULTS: The median age was 29 years (range 5-58). Most frequent tumor sites were thoracic and lumbar spine. All but three patients had nonmetastatic disease at diagnosis. Treatment included surgery and chemotherapy for all patients, 13 were also irradiated. Eight patients failed to achieve a macroscopically complete surgical remission (five local, one primary metastases, two both), six died, two are alive, both with radiotherapy. Of 12 patients with complete remission at all sites, three had a recurrence (two local, one metastases) and died. The median follow-up of the 11 survivors was 8.7 years (range 3.1-22.3), 5-year overall and event-free survival rates were 60% and 43%. Age <40 years, nonmetastatic disease at diagnosis and complete remission predicted for better overall survival (OS, P < 0.05). CONCLUSIONS: Osteosarcomas of the mobile spine are rare. With complete resection (and potentially radiotherapy) and chemotherapy, prognosis may be comparable with that of appendicular osteosarcomas.

Synthetic Database of Aortic Morphometry and Hemodynamics: Overcoming Medical Imaging Data Availability.

Modeling of hemodynamics and artificial intelligence have great potential to support clinical diagnosis and decision making. While hemodynamics modeling is extremely time- and resource-consuming, machine learning (ML) typically requires large training data that are often unavailable. The aim of this study was to develop and evaluate a novel methodology generating a large database of synthetic cases with characteristics similar to clinical cohorts of patients with coarctation of the aorta (CoA), a congenital heart disease associated with abnormal hemodynamics. Synthetic data allows use of ML approaches to investigate aortic morphometric pathology and its influence on hemodynamics. Magnetic resonance imaging data (154 patients as well as of healthy subjects) of aortic shape and flow were used to statistically characterize the clinical cohort. The methodology generating the synthetic cohort combined statistical shape modeling of aortic morphometry and aorta inlet flow fields and numerical flow simulations. Hierarchical clustering and non-linear regression analysis were successfully used to investigate the relationship between morphometry and hemodynamics and to demonstrate credibility of the synthetic cohort by comparison with a clinical cohort. A database of 2652 synthetic cases with realistic shape and hemodynamic properties was generated. Three shape clusters and respective differences in hemodynamics were identified. The novel model predicts the CoA pressure gradient with a root mean square error of 4.6 mmHg. In conclusion, synthetic data for anatomy and hemodynamics is a suitable means to address the lack of large datasets and provide a powerful basis for ML to gain new insights into cardiovascular diseases.

Towards improving the accuracy of aortic transvalvular pressure gradients: rethinking Bernoulli.

The transvalvular pressure gradient (TPG) is commonly estimated using the Bernoulli equation. However, the method is known to be inaccurate. Therefore, an adjusted Bernoulli model for accurate TPG assessment was developed and evaluated. Numerical simulations were used to calculate TPGCFD in patient-specific geometries of aortic stenosis as ground truth. Geometries, aortic valve areas (AVA), and flow rates were derived from computed tomography scans. Simulations were divided in a training data set (135 cases) and a test data set (36 cases). The training data was used to fit an adjusted Bernoulli model as a function of AVA and flow rate. The model-predicted TPGModel was evaluated using the test data set and also compared against the common Bernoulli equation (TPGB). TPGB and TPGModel both correlated well with TPGCFD (r > 0.94), but significantly overestimated it. The average difference between TPGModel and TPGCFD was much lower: 3.3 mmHg vs. 17.3 mmHg between TPGB and TPGCFD. Also, the standard error of estimate was lower for the adjusted model: SEEModel = 5.3 mmHg vs. SEEB = 22.3 mmHg. The adjusted model's performance was more accurate than that of the conventional Bernoulli equation. The model might help to improve non-invasive assessment of TPG. Graphical abstract Processing pipeline for the definition of an adjusted Bernoulli model for the assessment of transvalvular pressure gradient. Using CT image data, the patient specific geometry of the stenosed AVs were reconstructed. Using this segmentation, the AVA as well as the volume flow rate was calculated and used for model definition. This novel model was compared against classical approaches on a test data set, which was not used for the model definition.

Publisher Correction: Model-Based Therapy Planning Allows Prediction of Haemodynamic Outcome after Aortic Valve Replacement.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Model-Based Therapy Planning Allows Prediction of Haemodynamic Outcome after Aortic Valve Replacement.

Optimizing treatment planning is essential for advances in patient care and outcomes. Precisely tailored therapy for each patient remains a yearned-for goal. Cardiovascular modelling has the potential to simulate and predict the functional response before the actual intervention is performed. The objective of this study was to proof the validity of model-based prediction of haemodynamic outcome after aortic valve replacement. In a prospective study design virtual (model-based) treatment of the valve and the surrounding vasculature were performed alongside the actual surgical procedure (control group). The resulting predictions of anatomic and haemodynamic outcome based on information from magnetic resonance imaging before the procedure were compared to post-operative imaging assessment of the surgical control group in ten patients. Predicted vs. post-operative peak velocities across the valve were comparable (2.97 ± 1.12 vs. 2.68 ± 0.67 m/s; p = 0.362). In wall shear stress (17.3 ± 12.3 Pa vs. 16.7 ± 16.84 Pa; p = 0.803) and secondary flow degree (0.44 ± 0.32 vs. 0.49 ± 0.23; p = 0.277) significant linear correlations (p < 0.001) were found between predicted and post-operative outcomes. Between groups blood flow patterns showed good agreement (helicity p = 0.852, vorticity p = 0.185, eccentricity p = 0.333). Model-based therapy planning is able to accurately predict post-operative haemodynamics after aortic valve replacement. These validated virtual treatment procedures open up promising opportunities for individually targeted interventions.

Image-Based Personalization of Cardiac Anatomy for Coupled Electromechanical Modeling.

Computational models of cardiac electromechanics (EM) are increasingly being applied to clinical problems, with patient-specific models being generated from high fidelity imaging and used to simulate patient physiology, pathophysiology and response to treatment. Current structured meshes are limited in their ability to fully represent the detailed anatomical data available from clinical images and capture complex and varied anatomy with limited geometric accuracy. In this paper, we review the state of the art in image-based personalization of cardiac anatomy for biophysically detailed, strongly coupled EM modeling, and present our own tools for the automatic building of anatomically and structurally accurate patient-specific models. Our method relies on using high resolution unstructured meshes for discretizing both physics, electrophysiology and mechanics, in combination with efficient, strongly scalable solvers necessary to deal with the computational load imposed by the large number of degrees of freedom of these meshes. These tools permit automated anatomical model generation and strongly coupled EM simulations at an unprecedented level of anatomical and biophysical detail.

Sequential magnetic resonance monitoring of pulmonary flow with endovascular stents placed across the pulmonary valve in growing Swine.

BACKGROUND: Patients with endovascular stent implantation for the treatment of right ventricular outflow tract obstruction are often left with incomplete relief of the obstruction and significant pulmonary regurgitation. A noninvasive and reproducible method for monitoring such patients is desirable. MRI in the presence of a stent, however, has to overcome the problem of potential metallic artifacts. METHODS AND RESULTS: Under x-ray fluoroscopic guidance, endovascular nitinol stents were placed across the pulmonary valve in 6 young pigs to induce pulmonary regurgitation. Five additional pigs served as controls. Initial MRI was performed after 2 days (13.5+/-1.8 kg) and follow-up after 3 months (32+/-2.9 kg). Pulmonary flow volumes and regurgitant fraction were quantified by velocity-encoded cine (VEC) MRI through (VEC-TS) and distal to (VEC-DS) the stent. VEC-TS was compared with VEC-DS and volumetric measurements of left and right ventricular stroke volumes provided by cine MRI ("gold standard"). Antegrade and retrograde pulmonary flow volumes by VEC-TS were slightly but significantly less than those with VEC-DS and cine MRI. Excellent correlations (r>0.97) for phasic pulmonary flow volumes as measured by VEC-TS and VEC-DS were shown. Pulmonary regurgitant fraction increased from 32.8+/-15% to 49.6+/-17% (P<0.05) over the course of 3 months with VEC-TS. CONCLUSIONS: MRI demonstrates the progression of pulmonary regurgitation in growing swine. VEC MRI has the ability to quantify pulmonary blood flow inside the lumen of nitinol stents. MRI appears to be ideally suited for monitoring patients with endovascular nitinol stents in the pulmonary artery or pulmonary valve position.

Is MRI-based CFD able to improve clinical treatment of coarctations of aorta?

Pressure drop associated with coarctation of the aorta (CoA) can be successfully treated surgically or by stent placement. However, a decreased life expectancy associated with altered aortic hemodynamics was found in long-term studies. Image-based computational fluid dynamics (CFD) is intended to support particular diagnoses, to help in choosing between treatment options, and to improve performance of treatment procedures. This study aimed to prove the ability of CFD to improve aortic hemodynamics in CoA patients. In 13 patients (6 males, 7 females; mean age 25 ± 14 years), we compared pre- and post-treatment peak systole hemodynamics [pressure drops and wall shear stress (WSS)] vs. virtual treatment as proposed by biomedical engineers. Anatomy and flow data for CFD were based on MRI and angiography. Segmentation, geometry reconstruction and virtual treatment geometry were performed using the software ZIBAmira, whereas peak systole flow conditions were simulated with the software ANSYS(®) Fluent(®). Virtual treatment significantly reduced pressure drop compared to post-treatment values by a mean of 2.8 ± 3.15 mmHg, which significantly reduced mean WSS by 3.8 Pa. Thus, CFD has the potential to improve post-treatment hemodynamics associated with poor long-term prognosis of patients with coarctation of the aorta. MRI-based CFD has a huge potential to allow the slight reduction of post-treatment pressure drop, which causes significant improvement (reduction) of the WSS at the stenosis segment.

Mortality and morbidity in different immunization protocols for experimental autoimmune myocarditis in rats.

AIM: We aimed to investigate the histological and clinical presentations of experimental autoimmune myocarditis (EAM) induced by different immunization schemes. METHODS: Male young Lewis rats were divided into five groups immunized by porcine myocardial myosin: subcutaneously (SC) 2 mg (in two 1-mg doses on day 0 and 7), 0 mg (sham group) subcutaneously into rear footpads (RF), 0.25 mg RF, 0.5 mg RF or 1 mg RF (all RF once on day 0). On day 21, left ventricular (LV) function was assessed by cardiac magnetic resonance imaging and cardiac catheterization. The type and degree of myocardial inflammatory infiltrates were determined by conventional histology and immunohistochemistry. RESULTS: In the SC immunized rats and in the RF sham group, we observed 0% mortality, while in the actively RF immunized rats, mortality was 20, 20 and 44% for the 0.25 mg, 0.5 mg and 1 mg myosin doses respectively. Morbidity as defined by inflammatory infiltrates on haematoxylin and eosin (HE) staining was 22% in the SC immunized rats, 0% in the RF sham group and 100% in all actively RF immunized groups. We observed augmented relative ventricle weight and spleen weight, increased LV end-diastolic pressure, reduced LV developed pressure and reduced LV ejection fraction in all with myosin-immunized RF groups without any systematic dose effect. CONCLUSION: Subcutaneous immunization to the neck and flanks did not induce a reproducible EAM, while RF myosin administration reliably led to EAM. Lower myosin doses seem to induce the complete histological and clinical picture of EAM while being associated with lower mortality, non-specific symptoms and animal distress.

The impact of MRI-based inflow for the hemodynamic evaluation of aortic coarctation.

Aortic coarctation (CoA) accounting for 3-11% of congenital heart disease can be successfully treated. Long-term results, however, have revealed decreased life expectancy associated with abnormal hemodynamics. Accordingly, an assessment of hemodynamics is the key factor in treatment decisions and successful long-term results. In this study, 3D angiography whole heart (3DWH) and 4D phase-contrast magnetic resonance imaging (MRI) data were acquired. Geometries of the thoracic aorta with CoAs were reconstructed using ZIB-Amira software. X-ray angiograms were used to evaluate the post-treatment geometry. Computational fluid dynamics models in three patients were created to simulate pre- and post-treatment situations using the FLUENT program. The aim of the study was to investigate the impact of the inlet velocity profile (plug vs. MRI-based) with a focus on the peak systole pressure gradient and wall shear stress (WSS). Results show that helical flow at the aorta inlet can significantly affect the assessment of pressure drop and WSS. Simplified plug inlet velocity profiles significantly (p < 0.05) overestimate the pressure drop in pre- and post-treatment geometries and significantly (p < 0.05) underestimate surface-averaged WSS. We conclude that the use of the physiologically correct but time-expensive 4D MRI-based in vivo velocity profile in CFD studies may be an important step towards a patient-specific analysis of CoA hemodynamics.

Magnetic resonance imaging guided catheterisation for assessment of pulmonary vascular resistance: in vivo validation and clinical application in patients with pulmonary hypertension.

OBJECTIVES: To validate in vivo a magnetic resonance imaging (MRI) method for measurement of pulmonary vascular resistance (PVR) and subsequently to apply this technique to patients with pulmonary hypertension (PHT). METHODS AND RESULTS: PVR was assessed from velocity encoded cine MRI derived pulmonary artery (PA) flow volumes and simultaneously determined invasive PA pressures. For pressure measurements flow directed catheters were guided under magnetic resonance fluoroscopy at 1.5 T into the PA. In preliminary validation studies (eight swine) PVR was determined with the thermodilution technique and compared with PVR obtained by MRI (0.9 (0.5) v 1.1 (0.3) Wood units.m2, p = 0.7). Bland-Altman test showed agreement between both methods. Inter-examination variability was high for thermodilution (6.2 (2.2)%) but low for MRI measurements (2.1 (0.3)%). After validation, the MRI method was applied in 10 patients with PHT and five controls. In patients with PHT PVR was measured at baseline and during inhalation of nitric oxide. Compared with the control group, PVR was significantly increased in the PHT group (1.2 (0.8) v 13.1 (5.6) Wood units.m2, p < 0.001) but decreased significantly to 10.3 (4.6) Wood units.m2 during inhalation of nitric oxide (p < 0.05). Inter-examination variability of MRI derived PVR measurements was 2.6 (0.6)%. In all experiments (in vivo and clinical) flow directed catheters were guided successfully into the PA under MRI control. CONCLUSIONS: Guidance of flow directed catheters into the PA is feasible under MRI control. PVR can be determined with high measurement precision with the proposed MRI technique, which is a promising tool to assess PVR in the clinical setting.