Principles of Heart Valve Engineering

Arash Kheradvar

• Publisher: Academic Press
• Year: 2019
• ISBN:
  9780128146620
• Topic: Biological Sciences
• Subtopic: Biotechnology
• Index: Biological Sciences

Principles of Heart Valve Engineering is the first comprehensive resource for heart valve engineering that covers a wide range of topics, including biology, epidemiology, imaging and cardiovascular medicine. It focuses on valves, therapies, and how to develop safer and more durable artificial valves. The book is suitable for an interdisciplinary audience, with contributions from bioengineers and cardiologists that includes coverage of valvular and potential future developments. This book provides an opportunity for bioengineers to study all topics relating to heart valve engineering in a single book as written by subject matter experts.

• Covers the depth and breadth of this interdisciplinary area of research
• Encompasses a wide range of topics, from basic science, to the translational applications of heart valve engineering
• Contains contributions from leading experts in the field that are heavily illustrated

Chapter 1

Clinical anatomy and embryology of heart valves

Richard L. Goodwin ¹ , and Stefanie V. Biechler ^{2 1} Biomedical Sciences, University of South Carolina School of Medicine, Greenville, SC, United States ² Director of Marketing Collagen Solutions PLC Minneapolis, MN, United States

Abstract

Unidirectional blood flow is essential and the primary function of heart valves. Malformation and dysfunction of these complex structures result in potentially fatal pathologies. In this chapter, the formation, anatomy, and histology of the four cardiac valves will be described. These four cardiac valves can be further classified as two atrioventricular (AV) valves and two semilunar valves; however, each valve is unique. The two classes of valves differ in how the valve leaflets are supported when they are undergoing mechanical loading. To prevent regurgitation, the AV valves use a tension apparatus, which is composed of fibrocartilage-containing chordae tendineae (heart strings) and extensions of ventricular myocardium known as papillary muscles. On the other hand, the semilunar or ventriculoarterial valve leaflets are self-supporting, each having three leaflets that collapse onto thickened edges as they snap shut. Despite the differences in the adult cardiac valves, they appear to develop in similar ways. Both the AV and semilunar valve primordia appear early in heart development as acellular swellings between the primitive myocardium and the endocardium. These swellings or cushions are filled with proteoglycans and glycosaminoglycans making them jelly-like in consistency. During development, genetic and mechanical factors shape and remodel the soft cardiac cushions into tough, complex, fibrous tissues that are capable of withstanding the increasing demand as adult physiology is achieved. Increasing evidence supports a fundamental role for mechanical forces in the formation and homeostasis of valve tissues. However, much remains unknown about the specific molecular mechanisms that transduce the various forces which the valves are subjected to during the cardiac cycle. Defining these mechanisms will be a key in the development of new replacement valve technologies and novel therapeutic approaches to treating malformations and dysfunctions of cardiac valves.

Keywords

AV cushion; Chordae tendineae; ECM; Morphology; Semilunar valves; VIC

1. 1.1 Atrioventricular valves
   1. 1.1.1 Embryology
   2. 1.1.2 Morphology
   3. 1.1.3 Histology
2. 1.2 Semilunar valves
   1. 1.2.1 Embryology
   2. 1.2.2 Morphology
   3. 1.2.3 Histology
3. 1.3 Epigenetic factors in heart valve formation
4. References

1.1. Atrioventricular valves

1.1.1. Embryology

The heart is first formed as a simple tube from anterior lateral splanchnic mesoderm as the flat, trilaminar embryonic disc rolls into a cylinder. The growing prosencephalon and the closing gut tube endoderm bring the left and right lateral mesoderms together ventrally at the midline of the developing embryo [1]. At this stage or even a bit before, the primitive myocardium begins to spontaneously contract. The formation of the primitive heart tube is critical to further development of the embryo as it relies on effective hemodynamics to support the ontogenesis of other structures.

Though the cardiac valves play a central role in the maintenance of unidirectional blood flow for the entire cardiovascular system, other tissues have valves, including some veins and lymphatic vessels. It is important to note that a valve-like structure is formed, transiently, between the left and right atria known as the foramen ovale. This structure allows placentally derived oxygen- and nutrient-rich blood to pass from the right atrium to the left atrium, allowing it to be distributed systemically during fetal development. Following the first breath and perfusion of the pulmonary vascular, the blood pressure of the right side of the circulation drops below that of the systemic left side blood pressures, physiologically closing the foramen. Over time, the septum primum and the septum secundum fuse, leaving a thumbprint-shaped indentation on the atrial septum known as the fossa ovale. Failure of this foramen to close results in atrial septal defects of varying degree and severity.

The acelluar cushions are largely composed of the glycosaminoglycans hyaluronan and chondroitin sulfate, which yield a soft, jelly-like consistency, giving it the name, cardiac jelly (Fig. 1.1). Nonetheless these soft, pliable atrioventricular (AV) cushions do contribute to unidirectional blood flow in the early embryonic circulation. The myocardium of the AV junction produces the initial extracellular matrix (ECM) of the cushions. This provides the substrate that cells will use to migrate into the cushions and produce the tissues of the mature valves and supporting structures.

The majority of the cells populating the AV cushions are derived from endocardial cells of the inferior and superior AV cushions as well as significant contribution of epicardially derived cells that have undergone an epithelial-to-mesenchymal transformation (EMT) (Fig. 1.1C). During this process, cells detach from the simple epithelium that lines the interior and exterior of the heart and migrate into the matrix-filled cushions. The cells of this newly formed mesenchyme become VICs, which remodel and maintain the ECM into the complex, stratified valve leaflets [2]. The endocardial cells that cover the valves have been reported to retain their ability to undergo EMT throughout adult life [3]. Under pathological conditions, these endothelial cells transform and migrate into the mesenchyme of the valve leaflets and adversely contribute to valve disease. The roles that other cell types, such as macrophages and other immune cells, play in development and disease of valve tissues are beginning to gain increased attention by investigators, as they appear to be key regulators of homeostasis and pathology [4].

The inferior and superior AV cushions fuse, forming the septum intermedium, which physically separates the left (systemic) and right (pulmonary) sides of the circulatory system. As development continues, lateral AV cushions emerge on the left and right sides and fuse with the inferior and superior endocardial tissues, providing the cells that will go on to form the AV septum, AV valve leaflets, and supporting tissues. In lineage tracing studies, neural crest cells were detected in the AV septum and shown to have migrated from the top of the neural tube into the heart via pharyngeal arches 3, 4, and 6. The roles that specific cells play in the differentiation and their contributions to eventual adult cardiac structures are not clear despite intensive and ongoing efforts. It is critical that these studies be brought to their fruition, as defects in the AV valvuloseptal tissues are amongst the most lethal.

During normal development of the AV septum, the ostia of the atria anatomically align with the AV valves and the ventricular chambers. Subsequent fibroadipose development of the AV septum provides a foundation for the remodeling of the endocardial cushions into the valve leaflets. The AV septum and its fibrous cardiac skeleton also act as an electrical insulator that allows for the atrial, ventricular delay of the cardiac cycle. Housing the AV node of the cardiac conductance pathway, malformations of this region impact cardiac rhythm and function and are thus critically pathological.

Development of the valve leaflets and tension apparatus of AV valves is generally thought to be driven by a remodeling process in which cushion cells differentiate into ECM-producing VICs that create the stratified fibroelastic connective tissue of the valve leaflets and the fibrocartilage-like chordae tendineae. This remodeling occurs in humans during infancy and early childhood. The mechanisms that drive the differentiation of cells into VICs versus cells of the chordae tendineae are not clear [5]. Hemodynamically driven differentiation is an attractive, though, not well-tested mechanism. Malformations of these structures include prolapse, stenosis, and atresia.

The molecular mechanisms that create and maintain the tissues of the cardiac valves have a long history of investigation. Decades of research studies using a variety of model systems have delineated the molecular signaling pathways that are critical for the induction, differentiation, and maturation of cardiac valves [2,5]. These processes can be divided into four stages: endocardial cushion formation, endocardial transformation, growth and remodeling, and stratification (Fig. 1.2).

AV valve formation is initiated when the myocardium of the AV canal produces the cardiac jelly that fills the superior and inferior AV cushions. Along with the ECM proteins, these cells secrete morphogens that activate overlying endocardial cells to disconnect from neighboring endothelial cells and migrate into the ECM of the cushions. Myocardially derived BMP2 signals initiate transformation of the AV canal endocardial cells, while canonical Wnt and TGF-β signaling are critical for sustaining EMT [6]. Endocardially derived Notch and VEGF signaling are also required for EMT, and several other well-characterized signaling pathways that are summarized in Fig. 1.2.

In addition to the molecules above, transcription factors Twist1 and Tbx20 are critical for the proliferation and differentiation of newly formed mesenchymal cells. Interestingly, VEGF becomes a negative regulator of VIC proliferation at the post-EMT stage of valve development [6]. During this stage of valve development, the matricellular protein, periostin, becomes highly expressed in the developing cushions and is necessary for the differentiation of VICs into ECM-producing fibroblasts within valve cushions [2]. As its name denotes, periostin is also involved in bone development. In fact, valve development involves a number of molecules that have been implicated in the development of bone and cartilage. Another similarity between bone and cardiac valve development is the BMP-driven expression of Sox9 [6]. However, there is a tendon-like gene expression pattern in the differentiation of the chordae tendineae of AV valves, involving Fibroblast Growth Factor (FGF), scleraxis, and tenascin.

As the valve leaflets mature, they become more complex with specific combinations of ECM proteins deposited in different locations within the valve [2]. This results in the fo...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Contributors
• Preface
• Chapter 1. Clinical anatomy and embryology of heart valves
• Chapter 2. Heart valves' mechanobiology
• Chapter 3. Epidemiology of heart valve disease
• Chapter 4. Surgical heart valves
• Chapter 5. Transcatheter heart valves
• Chapter 6. Tissue-engineered heart valves
• Chapter 7. Computer modeling and simulation of heart valve function and intervention
• Chapter 8. In vitro experimental methods for assessment of prosthetic heart valves
• Chapter 9. Transvalvular flow
• Chapter 10. Heart valve leaflet preparation
• Chapter 11. Heart valve calcification
• Chapter 12. Immunological considerations for heart valve replacements
• Chapter 13. Polymeric heart valves
• Chapter 14. Regulatory considerations
• Appendix. Bernoulli’s equation, significance, and limitations
• Index