Coronary heart disease (CHD) is one of the leading causes of death every year with nearly three-fourths of all deaths caused by the disease. The challenge scientists are facing today is discovering new drugs to protect the heart against cellular damage caused by ischemia-reperfusion injury (I-R injury). Rapamycin is one such drug that has been shown to protect the heart against ischemia-induced cellular injury. Rapamycin(sirolimus) inhibits protein synthesis through inhibition of the mammalian target ofrapamycin (mTOR). This property of rapamycin has led to its current clinical applications in drug-eluting stents and in immunosuppresive treatment to organ transplant patients. The mechanism by which this drug protects against I-R injury is currently unknown. The goal of this study is to elucidate rapamycin's cardioprotective signaling pathway. We hypothesized that upregulation of Akt occurs possibly as part of a positive feedback mechanism following the inhibition of mTOR by rapamycin. Adult male ICRmice were treated with rapamycin (0.25 mg/kg, i.p.), or volume-matched DMSO (solvent for rapamycin), or rapamycin (0.25mg/kg, i.p.) plus wortmannin (WTN, 15µg/kg, i.p.),an inhibitor of phosphatidylinositol 3-kinase, or wortmannin alone (15µg/kg, i.p.). After 30 min of stabilization, the hearts were subjected to 20 minutes of global ischemia and 30 minutes of reperfusion in Langendorff model. In a separate series of experiments mice were either injected with DMSO or rapamycin for 30 minutes, 1 hour, and 2 hours before harvesting the hearts for Western blot analysis of levels of total or phosphorylated Akt at Ser473. Our results showed that rapamycin protected the heart as observed by a reductionin infarct size from 33.8 ± 2.0% in DMSO-treated hearts to 19.3 ± 4.1% in rapamycin-treated hearts; a 43% reduction. This infarct-limiting effect was completely blocked by wortmannin (29.3 ± 4.8%). However, Western blot analysis showed no change in the level of Akt phosphorylation after administration of rapamycin. Our current resultsfurther confirmed rapamycin as a potential cardio-therapeutic drug to limit infarct size,potentially through the PI3K signaling pathway. However, the exact signaling pathway of this protection still remains elusive.

Introduction. Computational modelling has been used widely in biological and clinical applications, but relatively less in surgical design and optimization. Magnetic resonance image (MRI)-based right ventricle (RV) models were introduced for patients with repaired Tetralogy of Fallot (rTOF) to assess ventricle cardiac function, and to identify morphological and mechanical parameters which can be used to predict and optimize post-surgery cardiac outcome. Tetralogy of Fallot is a common congenital heart defect which includes a ventricular septal defect and severe right ventricular outflow obstruction, account for the majority of cases with late onset RV failure. The current surgical approach for the patients with repaired ToF including pulmonary valve replacement/insertion (PVR) has yielded mixed results. It is of great interest to identify parameters which may be used to predict surgical cardiac function outcome after PVR. Data, Model, and Methods. Cardiac Magnetic Resonance (CMR) data from 20 healthy volunteers (11 males, mean year : 22.8) and 56 TOF patients (37 males, mean year : 25.3) were provided by Children's Hospital - Boston, Harvard Medical School from our NIH-funded project (R01 HL089269). RV wall thickness (WT), circumferential and longitudinal curvature (C-cur and L-cur), surface area (SA) and surface to volume ratio (SVR) were obtained based on CMR data for morphological analysis. 6 healthy volunteers and 16 TOF patients were chosen to construct 3D computational models for mechanical analysis. The 3D CMR-based RV/LV/Patch combination models included a) isotropic and anisotropic material properties, b) myocardial fiber orientation, c) active contraction with two zero-load geometries, and d) fluid-structure interactions. The models were used to obtain the assessment for RV mechanical conditions, which might be helpful for PVR surgical outcome prediction. All the computational models were built and solved in a commercial finite element software ADINA. Statistical methods including Linear Mixed- effort Method and Logistical regression were used in the morphological and mechanical analysis to find out potential indicators for predicting PVR outcome from the morphological and mechanical parameters. Results. In morphological analysis, statistically significant differences were found in RV SA and SVR between better-outcome patient group (BPG) and worse-outcome patient group (WPG). At begin of ejection, mean RV SA of BPG was 13.6% lower than that from WPG (241.1 cm2 v.s. 279.0 cm2, p =0.0161). Mean RV SVR of BPG was 13.1% lower than that from WPG (1.26 cm2/ml v.s. 1.45 cm2/ml, p =0.0271). Similar results were also found in RV SA and SVR at begin of filling. Furthermore, RV EF change from pre- to post-PVR were found negatively correlated with RV SA and SVR. In mechanical analysis, 22 structure-only models with one zero-load geometry (1G) were constructed to obtain stress/strain distributions. Stress-P1 from BPG was found to be closer to that from HG, compared to Stress- P1 of WPG. At the beginning of ejection, mean Stress-P1 of BPG was only 6.8% higher than that from healthy group (p =0.6889), while average Stress-P1 of WPG was 84.1% higher than that of healthy group (p =0.0418). Similar results were also found at begin of filling. The results suggested that comparing patients' RV stress values with healthy RV stress values may help identify patients with possible better outcome. The models with two zero-load geometries (2G models) and FSI models were also constructed. Their numerical results indicated that 2G models can provide end-ejection and end-filling results which were not available in 1G models, and FSI models can provide flow velocity, pressure and shear stress information which lacked in structure-only models (1G and 2G models). Conclusion. In vivo image-based 3D patient- specific computational models could lead to considerable potential gain not only in surgical design and outcome prediction, but also in understanding the mechanisms of RV failure for patients with repaired TOF.

No description available.

Heart disease is the leading cause of death in the world. Therefore, numerous studies are undertaken to identify indicators which can be applied to discover cardiac dysfunctions at an early age. Among others, the fluid dynamics of the blood flow (hemodymanics) is considered to contain relevant information related to abnormal performance of the heart.This thesis presents a robust framework for numerical simulation of the fluid dynamics of the blood flow in the left ventricle of a human heart and the fluid-structure interaction of the blood and the aortic leaflets.We first describe a patient-specific model for simulating the intraventricular blood flow. The motion of the endocardial wall is extracted from data acquired with medical imaging and we use the incompressible Navier-Stokes equations to model the hemodynamics within the chamber. We set boundary conditions to model the opening and closing of the mitral and aortic valves respectively, and we apply a stabilized Arbitrary Lagrangian-Eulerian (ALE) space-time finite element method to simulate the blood flow. Even though it is difficult to collect in-vivo data for validation, the available data and results from other simulation models indicate that our approach possesses the potential and capability to provide relevant information about the intraventricular blood flow.To further demonstrate the robustness and clinical feasibility of our model, a semi-automatic pathway from 4D cardiac ultrasound imaging to patient-specific simulation of the blood flow in the left ventricle is developed. The outcome is promising and further simulations and analysis of large data sets are planned.In order to enhance our solver by introducing additional features, the fluid solver is extended by embedding different geometrical prototypes of both a native and a mechanical aortic valve in the outflow area of the left ventricle.Both, the contact as well as the fluid-structure interaction, are modeled as a unified continuum problem using conservation laws for mass and momentum. To use this ansatz for simulating the valvular dynamics is unique and has the expedient properties that the whole problem can be described with partial different equations and the same numerical methods for discretization are applicable.All algorithms are implemented in the high performance computing branch of Unicorn, which is part of the open source software framework FEniCS-HPC. The strong advantage of implementing the solvers in an open source software is the accessibility and reproducibility of the results which enhance the prospects of developing a method with clinical relevance. / <p>QC 20171006</p>

Ekokardiografi (EKO) är en vanlig metod som används för bedömning och uppföljning av eventuella hjärtsjukdomar. Idag är tvådimensionell (2D) EKO standardmetoden för bestämning av slutdiastolisk volym (EDV), slutsystolisk volym (ESV) och ejektionsfraktionen (EF). Tredimensionell (3D) EKO har börjat användas mer kliniskt för bestämning av EDV, ESV och EF. Idag används två olika 3D mjukvaruprogram, Tomtec som är helautomatiserad och Dynamic Heart Model (DHM) som även den är helautomatiserad. Dessa används för bestämning av EDV, ESV och EF. Syftet med undersökningen var att jämföra två olika 3D-mjukvaruprogram, Tomtec samt DHM, för bestämning av EF och vänsterkammarvolymer (EDV och ESV). Dessa jämförs även med 2D som idag är standardmetod för värdering av både volymer och EF. Det erhölls signifikanta skillnader mellan programmen Tomtec och DHM, där högre volymer uppmättes med DHM. I jämförelse med 2D påvisades även signifikant större volymer med 3D (Tomtec och DHM). Resultatet från korrelationsanalysen visade en mycket hög korrelation mellan Tomtec och DHM för EDV, ESV och EF. Även en hög korrelation mellan 3D och 2D för bestämning av EDV, ESV och EF förelåg. Detta bekräftades med Bland Altman analyserna som visade goda överenstämmelser mellan Tomtec och DHM, samt mellan 3D och 2D. Överenstämmelserna mellan metoderna var hög. Mjukvaruprogrammen Tomtec och DHM stämmer väl överens med varandra och med 2D EKO. Skillnaden beror sannolikt på att Tomtec, DHM och 2D bygger på olika metodiker, däremot är denna skillnad obetydlig vid klinisk användning. / Echocardiography (ECHO) is a common method used for assessment and follow-up of possible heart diseases. Today, two-dimensional (2D) ECHO is the standard method for determining end-diastolic volume (EDV), end-systolic volume (ESV) and ejection fraction (EF). Currently, three-dimensional (3D) ECHO is used more clinically for the determination of EDV, ESV and EF. Two different 3D software are used today, Tomtec which is a fully automated method and Dynamic Heart Model (DHM) which is also a fully automated method. These are used to determine EDV, ESV and EF. The aim of the study was to compare two different 3D softwares, Tomtec and DHM, for assessment of EF and left ventricular volumes (EDV and ESV). These are also compared to 2D, which currently is the standard method for assessing both volumes and EF. Significant differences were seen between the Tomtec and DHM software, where higher volumes were measured with DHM.  In comparison with 2D, significantly larger volumes were obtained with 3D (Tomtec and DHM). The result from the correlation analysis showed very high correlation between Tomtec and DHM for EDV, ESV and EF. High correlation between 3D and 2D for determination of EDV, ESV and EF was present. This was confirmed with the Bland Altman analyses, which showed good agreement between Tomtec and DHM, as well as between 3D and 2D. Agreements between the methods were high. The Tomtec and DHM softwares showed good agreement as well as with 2D ECHO. The significant difference is probably because Tomtec, DHM and 2D are based on different methodologies, although in clinical practice this difference is of minor relevance.