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Annual Review of Biomedical Engineering Jul 2014In the past two decades, major advances have been made in the clinical evaluation and treatment of valvular heart disease owing to the advent of noninvasive cardiac... (Review)
Review
In the past two decades, major advances have been made in the clinical evaluation and treatment of valvular heart disease owing to the advent of noninvasive cardiac imaging modalities. In clinical practice, valvular disease evaluation is typically performed on two-dimensional (2D) images, even though most imaging modalities offer three-dimensional (3D) volumetric, time-resolved data. Such 3D data offer researchers the possibility to reconstruct the 3D geometry of heart valves at a patient-specific level. When these data are integrated with computational models, native heart valve biomechanical function can be investigated, and preoperative planning tools can be developed. In this review, we outline the advances in valve geometry reconstruction, tissue property modeling, and loading and boundary definitions for the purpose of realistic computational structural analysis of cardiac valve function and intervention.
Topics: Animals; Aortic Valve; Biomechanical Phenomena; Computer Simulation; Heart Valves; Humans; Imaging, Three-Dimensional; Mitral Valve; Models, Cardiovascular; Models, Statistical; Probability; Software; Tissue Distribution; Tissue Engineering
PubMed: 24819475
DOI: 10.1146/annurev-bioeng-071813-104517 -
Journal of the American Heart... Sep 2023Background Endocardial cells are a major progenitor population that gives rise to heart valves through endocardial cushion formation by endocardial to mesenchymal...
Background Endocardial cells are a major progenitor population that gives rise to heart valves through endocardial cushion formation by endocardial to mesenchymal transformation and the subsequent endocardial cushion remodeling. Genetic variants that affect these developmental processes can lead to congenital heart valve defects. and are ubiquitously expressed genes encoding cytoplasmic adaptors essential for cell signaling. This study aims to explore the specific role of and in the endocardial lineage during heart valve development. Methods and Results We deleted and specifically in the endocardial lineage. The resultant heart valve morphology was evaluated by histological analysis, and the underlying cellular and molecular mechanisms were investigated by immunostaining and quantitative reverse transcription polymerase chain reaction. We found that the targeted deletion of and impeded the remodeling of endocardial cushions at the atrioventricular canal into the atrioventricular valves. We showed that apoptosis was temporally increased in the remodeling atrioventricular endocardial cushions, and this developmentally upregulated apoptosis was repressed by deletion of and . Loss of and also resulted in altered extracellular matrix production and organization in the remodeling atrioventricular endocardial cushions. These morphogenic defects were associated with altered expression of genes in BMP (bone morphogenetic protein), connective tissue growth factor, and WNT signaling pathways, and reduced extracellular signal-regulated kinase signaling activities. Conclusions Our findings support that and have shared functions in the endocardial lineage that critically regulate atrioventricular valve development; together, they likely coordinate the morphogenic signals involved in the remodeling of the atrioventricular endocardial cushions.
Topics: Apoptosis; Catheters; Cytosol; Endocardium; Signal Transduction; Animals; Mice; Heart Valves
PubMed: 37702066
DOI: 10.1161/JAHA.123.029683 -
Developmental Biology Jun 2022Endothelial cells (ECs) are critical to proper heart valve development, directly contributing to the mesenchyme of the cardiac cushions, which progressively transform...
Endothelial cells (ECs) are critical to proper heart valve development, directly contributing to the mesenchyme of the cardiac cushions, which progressively transform into mature valves. To date, investigators have lacked sufficient markers of valve ECs to evaluate their contributions during valve morphogenesis fully. As a result, it has been unclear whether the well-characterized regional differentiation of valves correlates with any endothelial domains in the heart. Furthermore, it has been difficult to ascertain whether endothelial heterogeneity in the heart influences underlying mesenchymal zones in an angiocrine manner. To identify regionally expressed EC genes in the heart valves, we screened publicly available databases and assembled a toolkit of endothelial-enriched genes. We identified Cyp26b1 as one of many endothelial enriched genes found to be expressed in the endocardium of the developing cushions and valves. Here, we show that Cyp26b1 is required for normal heart valve development. Genetic ablation of Cyp26b1 in mouse embryos leads to abnormally thickened aortic valve leaflets, which is due in part to increased endothelial and mesenchymal cell proliferation in the remodeling valves. In addition, Cyp26b1 mutant hearts display ventricular septal defects (VSDs) in a portion of null embryos. We show that loss of Cyp26b1 results in upregulation of retinoic acid (RA) target genes, supporting the observation that Cyp26b1 has RA-dependent roles. Together, this work identifies a novel role for Cyp26b1 in heart valve morphogenesis and points to a role of RA in this process. Understanding the spatiotemporal expression dynamics of cardiac EC genes will pave the way for investigation of both normal and dysfunctional heart valve development.
Topics: Animals; Aortic Valve; Endothelial Cells; Heart Valves; Mice; Morphogenesis; Organogenesis; Retinoic Acid 4-Hydroxylase; Tretinoin
PubMed: 35364055
DOI: 10.1016/j.ydbio.2022.03.003 -
Medicina (Kaunas, Lithuania) Nov 2022Developing a prosthetic heart valve that combines the advantageous hemodynamic properties of its biological counterpart with the longevity of mechanical prostheses has...
Developing a prosthetic heart valve that combines the advantageous hemodynamic properties of its biological counterpart with the longevity of mechanical prostheses has been a major challenge for heart valve development. Anatomically inspired artificial polymeric heart valves have the potential to combine these beneficial properties, and innovations in 3D printing have given us the opportunity to rapidly test silicone prototypes of new designs to further the understanding of biophysical properties of artificial heart valves. TRISKELION is a promising prototype that we have developed, tested, and further improved in our institution. Materials and STL files of our prototypes were designed with FreeCad 0.19.2 and 3D printed with an Agilista 3200W (Keyence, Osaka, Japan) using silicones of Shore hardness 35 or 65. Depending on the valve type, the support structures were printed in AR-M2 plastics. The prototypes were then tested using a hemodynamic pulse duplicator (HKP 2.0) simulating an aortic valve cycle at 70 bpm with 70 mL stroke volume (cardiac output 4.9 L/min). Valve opening cycles were visualized with a high-speed camera (Phantom Miro C320). The resulting values led to further improvements of the prototype (TRISKELION) and were compared to a standard bioprosthesis (Edwards Perimount 23 mm) and a mechanical valve (Bileaflet valve, St. Jude Medical). : We improved the silicone prototype with currently used biological and mechanical valves measured in our setup as benchmarks. The regurgitation fractions were 22.26% ± 4.34% (TRISKELION) compared to 8.55% ± 0.22% (biological) and 13.23% ± 0.79% (mechanical). The mean systolic pressure gradient was 9.93 ± 3.22 mmHg (TRISKELION), 8.18 ± 0.65 mmHg (biological), and 10.15 ± 0.16 mmHg (mechanical). The cardiac output per minute was at 3.80 ± 0.21 L/min (TRISKELION), 4.46 ± 0.01 L/min (biological), and 4.21 ± 0.05 L/min (mechanical). The development of a heart valve with a central structure proves to be a promising concept. It offers another principle to address the problem of longevity in currently used heart valves. Using 3D printing to develop new prototypes provides a fast, effective, and accurate way to deepen understanding of its physical properties and requirements. This opens the door for translating and combining results into modern prototypes using highly biocompatible polymers, internal structures, and advanced valve layouts.
Topics: Humans; Heart Valves; Printing, Three-Dimensional; Polymers; Heart Valve Prosthesis; Silicones
PubMed: 36422234
DOI: 10.3390/medicina58111695 -
Circulation Research Sep 2004During the past decade, single gene disruption in mice and large-scale mutagenesis screens in zebrafish have elucidated many fundamental genetic pathways that govern... (Review)
Review
During the past decade, single gene disruption in mice and large-scale mutagenesis screens in zebrafish have elucidated many fundamental genetic pathways that govern early heart patterning and differentiation. Specifically, a number of genes have been revealed serendipitously to play important and selective roles in cardiac valve development. These initially surprising results have now converged on a finite number of signaling pathways that regulate endothelial proliferation and differentiation in developing and postnatal heart valves. This review highlights the roles of the most well-established ligands and signaling pathways, including VEGF, NFATc1, Notch, Wnt/beta-catenin, BMP/TGF-beta, ErbB, and NF1/Ras. Based on the interactions among and relative timing of these pathways, a signaling network model for heart valve development is proposed.
Topics: Animals; Cell Differentiation; Endothelial Cells; Endothelium, Vascular; Heart Valves; Humans; Mice; Models, Cardiovascular; Proteins; Signal Transduction
PubMed: 15345668
DOI: 10.1161/01.RES.0000141146.95728.da -
Journal of Cardiovascular Magnetic... Jan 2012Cardiovascular magnetic resonance (CMR) has become a valuable investigative tool in many areas of cardiac medicine. Its value in heart valve disease is less well... (Review)
Review
Cardiovascular magnetic resonance (CMR) has become a valuable investigative tool in many areas of cardiac medicine. Its value in heart valve disease is less well appreciated however, particularly as echocardiography is a powerful and widely available technique in valve disease. This review highlights the added value that CMR can bring in valve disease, complementing echocardiography in many areas, but it has also become the first-line investigation in some, such as pulmonary valve disease and assessing the right ventricle. CMR has many advantages, including the ability to image in any plane, which allows full visualisation of valves and their inflow/outflow tracts, direct measurement of valve area (particularly for stenotic valves), and characterisation of the associated great vessel anatomy (e.g. the aortic root and arch in aortic valve disease). A particular strength is the ability to quantify flow, which allows accurate measurement of regurgitation, cardiac shunt volumes/ratios and differential flow volumes (e.g. left and right pulmonary arteries). Quantification of ventricular volumes and mass is vital for determining the impact of valve disease on the heart, and CMR is the 'Gold standard' for this. Limitations of the technique include partial volume effects due to image slice thickness, and a low ability to identify small, highly mobile objects (such as vegetations) due to the need to acquire images over several cardiac cycles. The review examines the advantages and disadvantages of each imaging aspect in detail, and considers how CMR can be used optimally for each valve lesion.
Topics: Heart Valve Diseases; Heart Valves; Hemodynamics; Humans; Magnetic Resonance Imaging; Predictive Value of Tests; Prognosis; Reproducibility of Results
PubMed: 22260363
DOI: 10.1186/1532-429X-14-7 -
International Journal of Molecular... Feb 2023The development of a novel artificial heart valve with outstanding durability and safety has remained a challenge since the first mechanical heart valve entered the... (Review)
Review
The development of a novel artificial heart valve with outstanding durability and safety has remained a challenge since the first mechanical heart valve entered the market 65 years ago. Recent progress in high-molecular compounds opened new horizons in overcoming major drawbacks of mechanical and tissue heart valves (dysfunction and failure, tissue degradation, calcification, high immunogenic potential, and high risk of thrombosis), providing new insights into the development of an ideal artificial heart valve. Polymeric heart valves can best mimic the tissue-level mechanical behavior of the native valves. This review summarizes the evolution of polymeric heart valves and the state-of-the-art approaches to their development, fabrication, and manufacturing. The review discusses the biocompatibility and durability testing of previously investigated polymeric materials and presents the most recent developments, including the first human clinical trials of LifePolymer. New promising functional polymers, nanocomposite biomaterials, and valve designs are discussed in terms of their potential application in the development of an ideal polymeric heart valve. The superiority and inferiority of nanocomposite and hybrid materials to non-modified polymers are reported. The review proposes several concepts potentially suitable to address the above-mentioned challenges arising in the R&D of polymeric heart valves from the properties, structure, and surface of polymeric materials. Additive manufacturing, nanotechnology, anisotropy control, machine learning, and advanced modeling tools have given the green light to set new directions for polymeric heart valves.
Topics: Humans; Heart Valve Prosthesis; Heart Valves; Biocompatible Materials; Prosthesis Design; Polymers; Bioprosthesis
PubMed: 36835389
DOI: 10.3390/ijms24043963 -
PLoS Genetics Feb 2019Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for...
Heart valve disease is a major clinical problem worldwide. Cardiac valve development and homeostasis need to be precisely controlled. Hippo signaling is essential for organ development and tissue homeostasis, while its role in valve formation and morphology maintenance remains unknown. VGLL4 is a transcription cofactor in vertebrates and we found it was mainly expressed in valve interstitial cells at the post-EMT stage and was maintained till the adult stage. Tissue specific knockout of VGLL4 in different cell lineages revealed that only loss of VGLL4 in endothelial cell lineage led to valve malformation with expanded expression of YAP targets. We further semi-knockout YAP in VGLL4 ablated hearts, and found hyper proliferation of arterial valve interstitial cells was significantly constrained. These findings suggest that VGLL4 is important for valve development and manipulation of Hippo components would be a potential therapy for preventing the progression of congenital valve disease.
Topics: Animals; Cell Lineage; Cell Proliferation; Endothelial Cells; Epithelial-Mesenchymal Transition; Gene Expression Regulation, Developmental; Gene Knockout Techniques; Heart Valves; Hippo Signaling Pathway; Homeostasis; Hypertrophy, Left Ventricular; Mice; Protein Serine-Threonine Kinases; Signal Transduction; Transcription Factors
PubMed: 30789911
DOI: 10.1371/journal.pgen.1007977 -
Annals of Biomedical Engineering Dec 2006Potential applications of tissue engineering in regenerative medicine range from structural tissues to organs with complex function. This review focuses on the... (Review)
Review
Potential applications of tissue engineering in regenerative medicine range from structural tissues to organs with complex function. This review focuses on the engineering of heart valve tissue, a goal which involves a unique combination of biological, engineering, and technological hurdles. We emphasize basic concepts, approaches and methods, progress made, and remaining challenges. To provide a framework for understanding the enabling scientific principles, we first examine the elements and features of normal heart valve functional structure, biomechanics, development, maturation, remodeling, and response to injury. Following a discussion of the fundamental principles of tissue engineering applicable to heart valves, we examine three approaches to achieving the goal of an engineered tissue heart valve: (1) cell seeding of biodegradable synthetic scaffolds, (2) cell seeding of processed tissue scaffolds, and (3) in-vivo repopulation by circulating endogenous cells of implanted substrates without prior in-vitro cell seeding. Lastly, we analyze challenges to the field and suggest future directions for both preclinical and translational (clinical) studies that will be needed to address key regulatory issues for safety and efficacy of the application of tissue engineering and regenerative approaches to heart valves. Although modest progress has been made toward the goal of a clinically useful tissue engineered heart valve, further success and ultimate human benefit will be dependent upon advances in biodegradable polymers and other scaffolds, cellular manipulation, strategies for rebuilding the extracellular matrix, and techniques to characterize and potentially non-invasively assess the speed and quality of tissue healing and remodeling.
Topics: Animals; Bioartificial Organs; Bioprosthesis; Heart Valve Diseases; Heart Valve Prosthesis; Heart Valves; Humans; Tissue Engineering
PubMed: 17053986
DOI: 10.1007/s10439-006-9163-z -
Annals of Biomedical Engineering Jun 2020The scarcity of data available on the best approach for pulmonary fetal valve replacement or implantation necessitate an investigation on whether practices using adult...
The scarcity of data available on the best approach for pulmonary fetal valve replacement or implantation necessitate an investigation on whether practices using adult transcatheter valves could be translated to fetal applications. The objective of this study is to evaluate the hemodynamic characteristics and the turbulent properties of a fetal sized trileaflet transcatheter pulmonary valve in comparison with an adult balloon-expandable valve in order to assess the possibility of designing valves for fetal applications using dynamic similarity. A 6 mm fetal trileaflet valve and a 26 mm SAPIEN 3 valve were assessed in a pulse duplicator. Particle image velocimetry was performed. Pressure gradient (ΔP), effective orifice area (EOA), regurgitant fractions (RF), pinwheeling indices (PI) and turbulent stresses were evaluated. ΔP was 8.56 ± 0.139 and 7.76 ± 0.083 mmHg with fetal valve and SAPIEN respectively (p < 0.0001); EOA was 0.10 ± 0.0007 and 2.1 ± 0.025 cm with fetal valve and SAPIEN respectively (p < 0.0001); RF with the fetal valve was 2.35 ± 1.99% and with SAPIEN 10.92 ± 0.11% (p < 0.0001); PI with fetal valve was 0.404 ± 0.01 and with SAPIEN 0.37 ± 0.07; The flow regime with the fetal valve was turbulent and Reynolds numbers reached about 7000 while those with the SAPIEN reached about 20,000 at peak velocity. Turbulent stresses were significantly higher with fetal valve compared with SAPIEN. Instantaneous viscous shear stresses with fetal valve were 5.8 times higher than those obtained with SAPIEN and Reynolds shear stresses were 2.5 times higher during peak systole. The fetal valve implantation leads to a turbulent flow (specific to this particular type and design of valve) regime unlike what is expected of a small valve with different flow properties compared to adult valves.
Topics: Adult; Alloys; Aluminum; Fetus; Heart Valve Prosthesis; Heart Valve Prosthesis Implantation; Heart Valves; Hemodynamics; Humans; Stress, Mechanical; Zinc
PubMed: 32052320
DOI: 10.1007/s10439-020-02475-3