Hemodynamics in CHD: mechanical regulation of congenital heart defects

European Commission Seventh Framework (FP7) People Programme Marie Curie Actions; Project No: PIRG08-GA-2010-276987; Project Budget: 100,000 Euros; Project Duration: April 2011 – April 2013This is the periodic report for the HEMODYNAMICS IN CHD project, which received funding under the Seventh Framework Programme (FP7). The project will be applying the techniques developed in to a well established animal model for a severe CHD, hypoplastic left heart syndrome, to dissect the contribution of blood flow related forces on this disease. The report includes images generated to study embryonic development of congenital heart defects.European Commussio

Investigation of potential rupture locations for abdominal aortic aneurysms with patient-specific computational fluid dynamic analysis approach

Background: About 18 million people die each year from cardiovascular disorders, accounting for 31% of all deaths worldwide. Abdominal Aortic Aneurysm (AAA) is a serious clinical condition manifested as dilation of the aorta beyond 50% of the normal vessel diameter. Current clinical practice is to surgically repair large AAAs with a diameter > 5.5 cm. However, the practice is questionable based on small AAA rupture and large AAA no rupture cases. Currently, there is no accepted technique to quantify the risk of rupture for individual AAAs. It is believed that rupture locations are where peak wall stresses act. Hemodynamic forces by the flowing blood such as shear stress are also thought to contribute to the formation of aneurysms leading to rupture. Aim: Our aim is to perform precise computational analysis for the assessment of rupture risk for AAA patients. Methods: In this IRCC funded project, we will develop a patient-specific computational modeling methodology to assess wall stresses acting on the diseased AAA, for reliable rupture risk assessment of the conditions. In the computational simulations, we will adapt the fluid-structure interaction approach to account for both tissue displacements and hemodynamic forces, for enhanced accuracy. We have recruited 20 AAA patients at HMC and collected CT scans and ultrasound images for these patients. Using these medical data, we are developing accurate 3D model geometries. Doppler ultrasound measurements are used as velocity boundary conditions in the simulations. Expected Results: Findings from this project will contribute significantly to understanding the biomechanics and mechanobiology of AAA rupture and will help to establish a computational modeling approach for rupture risk assessment of AAAs

Mechanical regulation of cardiac development

Mechanical forces are essential contributors to and unavoidable components of cardiac formation, both inducing and orchestrating local and global molecular and cellular changes. Experimental animal studies have contributed substantially to understanding the mechanobiology of heart development. More recent integration of high-resolution imaging modalities with computational modeling has greatly improved our quantitative understanding of hemodynamic flow in heart development. Merging these latest experimental technologies with molecular and genetic signaling analysis will accelerate our understanding of the relationships integrating mechanical and biological signaling for proper cardiac formation. These advances will likely be essential for clinically translatable guidance for targeted interventions to rescue malforming hearts and/or reconfigure malformed circulations for optimal performance. This review summarizes our current understanding on the levels of mechanical signaling in the heart and their roles in orchestrating cardiac development

An ex-ovo chicken embryo culture system suitable for imaging and microsurgery applications

Yalçın, Hüseyin Çağatay (Dogus Author)Understanding the relationships between genetic and microenvironmental factors that drive normal and malformed embryonic development is fundamental for discovering new therapeutic strategies. Advancements in imaging technology have enabled quantitative investigation of the organization and maturing of the body plan, but later stage embryonic morphogenesis is less clear. Chicken embryos are an attractive vertebrate animal model system for this application because of its ease of culture and surgical manipulation. Early embryos can be cultured for a short time on filter paper rings, which enables complete optical access for cell patterning and fate studies. Studying advanced developmental processes such as cardiac morphogenesis are traditionally performed through a window of the eggshell, but this technique limits optical access due to window size. We previously developed a simple method to culture whole embryos ex-ovo on hexagonal weigh boats for up to 10 days, which enabled high resolution imaging via ultrasonography. These cultures were difficult to transport, limiting the types of imaging tools available for live experiments. We here present an improved shell-less culture system with a cost-effective, portable environmental chamber. Eggs were cracked onto a hammock created by a polyurethane membrane (cling wrap) affixed circumferentially to a plastic cup partially filled with sterile water. The dimensions of the circumference and depth of the hammock were both critical to maintain surface tension, while the mechanics of the hammock and water beneath helped dampen vibrations induced by transportation. A small footprint circulating water bath was also developed to enable continuous temperature control during experimentation. We demonstrate the ability to culture embryos in this way for at least 14 days without morphogenic defect or delay and employ this system in several microsurgical and imaging applications

Two-photon microscopy-guided femtosecond-laser photoablation of avian cardiogenesis: Noninvasive creation of localized heart defects

Yalçın, Hüseyin Çağatay (Dogus Author)Embryonic heart formation is driven by complex feedback between genetic and hemodynamic stimuli. Clinical congenital heart defects (CHD), however, often manifest as localized microtissue malformations with no underlying genetic mutation, suggesting that altered hemodynamics during embryonic development may play a role. An investigation of this relationship has been impaired by a lack of experimental tools that can create locally targeted cardiac perturbations. Here we have developed noninvasive optical techniques that can modulate avian cardiogenesis to dissect relationships between alterations in mechanical signaling and CHD. We used two-photon excited fluorescence microscopy to monitor cushion and ventricular dynamics and femtosecond pulsed laser photoablation to target micrometer-sized volumes inside the beating chick hearts. We selectively photoablated a small (∼100 μm radius) region of the superior atrioventricular (AV) cushion in Hamburger-Hamilton 24 chick embryos. We quantified via ultrasound that the disruption causes AV regurgitation, which resulted in a venous pooling of blood and severe arterial constriction. At 48 h postablation, quantitative X-ray microcomputed tomography imaging demonstrated stunted ventricular growth and pronounced left atrial dilation. A histological analysis demonstrated that the laser ablation produced defects localized to the superior AV cushion: a small quasispherical region of cushion tissue was completely obliterated, and the area adjacent to the myocardial wall was less cellularized. Both cushions and myocardium were significantly smaller than sham-operated controls. Our results highlight that two-photon excited fluorescence coupled with femtosecond pulsed laser photoablation should be considered a powerful tool for studying hemodynamic signaling in cardiac morphogenesis through the creation of localized microscale defects that may mimic clinical CHD

Femtosecond laser photodisruption of vitelline vessels of avian embryos as a technique to study embryonic vascular remodeling

During cardiogenesis, congenital heart defects (CHDs), generally start as local tissue abnormalities without underlying genetic causes, suggesting abnormal hemodynamics may be an important source. Due to the scarcity of experimental techniques that permits the formation of minimally-invasive and well-controlled cardiac perturbations, experimental investigation of embryonic development of CHD via in-vivo models is difficult. In this study, in order to investigate the relationship between abnormal mechanical signaling and embryonic CHD development, a previously developed laser-based technique was adopted to alter chicken embryonic cardiovascular development. The technique incorporates two-photon fluorescence microscopy to visualize deep tissue while femtosecond-pulsed laser photodisruption is used to ablate targeted tissue. Vitelline vessel remodeling under abnormal hemodynamics was the prime concern of the study. In order to alter the hemodynamics, blood flowing inside 50-300 mm diameter Hamburger-Hamilton 24 embryonic vessels was selectively ablated. Red blood cells in the blood and endothelial cells of the vessel walls were damaged as a result of ablation. Cellular injuries led to micro-occlusions in the vessels. Several micro-occlusions formed stable clots, resulting in a complete cessation of blood flow in the targeted vessels. By measuring blood velocities in the surrounding vessels via line scanning technique, the subsequent redistribution of blood flow in the immediate upstream and downstream vessels was revealed. The network was analyzed after 24 h, and it was found to be degraded. Degradation of the entire network can be attributed to the abnormalities in hemodynamics within the vessels. For studying embryonic development of heart defects under disturbed flow conditions, the present study can be extended to clot a blood vessel inside the embryo or a vitelline vessel in the vicinity of the heart. These results demonstrate that, laser-based noninvasive tools should be considered as powerful techniques to analyze hemodynamic signals encountered in embryonic development of CHD

Numerical assessament of turbulent flow downstream of stenosed aortic valve with flexible leaflets using fluid-solid interactions approach

Yalçın, Hüseyin Çağatay (Dogus Author) -- Conference full title: 2014 IEEE International Conference on Bioinformatics and Bioengineering (BIBE) 10-12 Nov. 2014, Boca Raton, Florida, USA.Aortic valve stenosis can trigger regions of turbulent flow downstream of the aortic valve. This disturbed blood flow in this region can cause tissue damages due to increased levels of turbulent shear stress. The aim of the present work was to investigate the effect of aortic stenosis on turbulence parameters of the blood flow over flexible leaflets of aortic valve. In this study the turbulent flow was simulated numerically using k-ε realizable model. The interaction between fluid and structure fields was applied using an implicit iterative method. To characterize the turbulent intensity, turbulent kinetic energy was computed. The results show that the levels of turbulence increases with more severe stenosed valves. The results also revealed that the flexible behavior of the leaflets of the aortic valve can also disturb the flow which can produce regions of turbulence downstream of the aortic valve

Patient Specific Transcatheter Aortic Valve Replacement Therapy Pathway with Computational Fluid Structure Interaction Analysis

Total cardiovascular disease (CVD) prevalence has risen dramatically from 271 million in 1990 to 523 million in 2019, and CVD fatalities rose gradually from 12.1 million in 1990 to 18.6 million in 2019. According to American Heart Association statistics, annual heart valve procedures in the United States were above 100,000 in 2013, with approximately 50,000 AV replacements. The ideal replacement valve should be durable, resistant to thrombosis, and have excellent hemodynamics features. Transcatheter aortic valve replacement (TAVR) has been introduced about two decades ago as an alternative for minimally invasive implantation of new generation bioprosthetic heart valves. Computational modeling can be used during therapy planning for the selection of appropriate replacement valves for TAVR. In this NPRP funded project, we are establishing a mechanical and FSI analysis path, for a detailed patient-specific hemodynamics analysis for TAVR, considering the most important parameters affecting TAV efficiency. This approach will enable the choice of the most suitable TAV type and deployment position for the treatment. TAV which is crimped and placed into the catheter by mechanical analysis is deployed in a patient-specific geometry in a virtual treatment then contact pressure and the stress are measured on the aortic root, stent, and aortic leaflets. TAV performance indicators are determined by FSI analysis using coupled ABAQUS and Flow-vision software. With this advanced analysis and simulation path, we expect to estimate accurately the clinical TAVR parameters such as contact pressure, contact area, principal stress, etc. before the operation during therapy planning. This approach will help clinicians in optimal valve selection for TAVR patients

Numerical investigation of influence of leaflet calcification on aortic valve hemodynamics

Conference: International Conference on Numerical Analysis and Applied Mathematics (ICNAAM) -- Location: Rhodes, GREECE -- Date: SEP 22-28, 2014In this study influence of leaflet calcification on Aortic Valve calcification was studied using fluid solid interactions approach. The leaflets of the aortic valve were modeled as flexible structure. The interaction between flexible leaflets and blood flow was modeled with an iterative implicit method. The time averaged wall shear stress and pressure drop parameters were calculated for different models with various Young Modulus of elasticity for leaflets. Results revealed that more calcified leaflets are imposed to more wall shear stress and higher levels of pressure drop

Hemodynamic patterning of the avian atrioventricular valve

Yalçın, Hüseyin Çağatay (Dogus Author)In this study, we develop an innovative approach to rigorously quantify the evolving hemodynamic environment of the atrioventricular (AV) canal of avian embryos. Ultrasound generated velocity profiles were imported into Micro-Computed Tomography generated anatomically precise cardiac geometries between Hamburger-Hamilton (HH) stages 17 and 30. Computational fluid dynamic simulations were then conducted and iterated until results mimicked in vivo observations. Blood flow in tubular hearts (HH17) was laminar with parallel streamlines, but strong vortices developed simultaneous with expansion of the cushions and septal walls. For all investigated stages, highest wall shear stresses (WSS) are localized to AV canal valve-forming regions. Peak WSS increased from 19.34 dynes/cm(2) at HH17 to 287.18 dynes/cm(2) at HH30, but spatiotemporally averaged WSS became 3.62 dynes/cm(2) for HH17 to 9.11 dynes/cm(2) for HH30. Hemodynamic changes often preceded and correlated with morphological changes. These results establish a quantitative baseline supporting future hemodynamic analyses and interpretations. Developmental Dynamics 240: 23-35, 2011