Preface

Valvular heart diseases represent an underappreciated yet serious and growing problem. Due to population aging, calcific aortic valve disease (CAVD) has become the most common heart valve disease in developed and rapidly developing regions of the world, affecting ap‐ proximately 25% of adults over 65 years of age. No therapies exist to slow this disease pro‐ gression, and surgical valve replacement is the only effective treatment. More than 275,000 aortic valve replacements are performed annually worldwide, and this number is expected to triple by 2050. Although rheumatic heart disease continues to be an important problem in developing countries, its prevalence has generally declined. This book will address CAVD as a common heart valve disease, focusing predominantly on the underlying mechanisms and current treatment approaches. We hope that this book will enable readers to grasp the current knowledge and focus on the possibility of preventing disease progression in the near future.

The book is divided into six sections and comprised of 18 chapters written by well-recog‐ nized investigators from United States, Europe, and Asia. Section I focuses on the biology and function of the normal aortic valve. Chapter 1 is written by a research group lead by Dr. K. Jane Grande-Allen, a renowned investigator in the field of cardiac valve extracellular ma‐ trix and valve biology. It describes the role of major and minor matrices in normal valves, focusing on extracellular matrix function and biomechanical properties. Chapter 2, written by Prof. Tilea Ioan, deals with the anatomy and function of normal aortic valve components. Section II provides current insight into the mechanisms of CAVD. It begins with Chapter 3, written by Prof. Katherine Yutzey, a prominent scholar in valve developmental biology, who provides an overview of signaling pathways involved in valve development and their reactivation during CAVD progression. This chapter also describes osteogenic-related mo‐ lecular pathways involved in CAVD, and provides an outlook on developing therapeutics to treat CAVD. The next two chapters (Chapter 4, written by Dr. Erik Fung, and Chapter 5, written by Dr. Claudia Goettsch) offer evolving insights into the mechanisms of CAVD, in‐ cluding NOTCH signaling and microRNA dysregulation. Topics covered in Section III in‐ clude proteomics and metabolomics in Chapter 6, written by Dr. Maria Barderas; and genetics in Chapter 7, written by Dr. Robert Hinton. Both chapters represent innovative technology platforms recently developed to identify DNA, RNA, proteins, and peptides in different biological compartments, which could serve as biomarkers for various diseases. Section IV reviews advances in the field of heart valve tissue engineering and is comprised of two chapters written by leaders in the field (Chapter 8, written by Prof. Carlijn Bouten, and Chapter 9, written by Prof. Gino Gerosa). New cutting-edge approaches, including heart valve tissue engineering and tissue-guided regeneration, have been proposed to over‐ come the limitations of current valve substitutes. These chapters describe the foreign body

response to implantation of biomaterials, preclinical and clinical models, principles of tissue engineering, and strategies to improve viable and functional aortic valve substitutes. Section V provides comprehensive information on bicuspid aortic valve (BAV) disease, in Chapter 10, written by Dr. George Tokmaji, and Chapter 11, written by Dr. Mehmed Demir. This section covers the diagnosis, treatment, and complications of BAV disease, and is particular‐ ly important because BAV is a common congenital cardiac abnormality affecting 2% of the population, and presenting in 50% of adults undergoing valve replacement for severe CAVD. Finally, Section VI is comprised of seven chapters written by an international team, including Drs. Velicki Lazar, Oz Fahrettin, Karali Kaan, Juan Bustamate, Akin Ibrahim, and Kazumasa Orihashi, and covers different aspects of CAVD treatment options, including the recently developed transcatheter aortic valve implantation. Chapter 18, written by Hideaki Senzaki on congenital aortic stenosis in pediatric patients, closes this section.

This book will provide the most up-to-date knowledge in the fast-growing and ever-chang‐ ing field of aortic valve pathobiology. We hope that it will be useful for cardiologists, cardio‐ vascular surgeons, fellows, and scientists who, we believe, should always be searching for updates in diagnosis, treatment, and research advancement. This open-access book will pro‐ vide the most current information on CAVD.

I acknowledge my mentors — Dr. Frederick J. Schoen, for introducing me to the exciting biology of cardiac valve disease, and Dr. Peter Libby, for his continuous support and inspi‐ ration. And I can never thank my family enough — especially my husband, Dr. Masanori Aikawa, for believing in me and encouraging me throughout my career.

> **Elena Aikawa, MD, PhD** Associate Professor of Medicine Harvard Medical School Director, Vascular Biology Program Center for Interdisciplinary Cardiovascular Sciences Brigham and Women's Hospital Boston, USA

**Section 1**

**Biology and Function of Normal Aortic Valve**

**Biology and Function of Normal Aortic Valve**

response to implantation of biomaterials, preclinical and clinical models, principles of tissue engineering, and strategies to improve viable and functional aortic valve substitutes. Section V provides comprehensive information on bicuspid aortic valve (BAV) disease, in Chapter 10, written by Dr. George Tokmaji, and Chapter 11, written by Dr. Mehmed Demir. This section covers the diagnosis, treatment, and complications of BAV disease, and is particular‐ ly important because BAV is a common congenital cardiac abnormality affecting 2% of the population, and presenting in 50% of adults undergoing valve replacement for severe CAVD. Finally, Section VI is comprised of seven chapters written by an international team, including Drs. Velicki Lazar, Oz Fahrettin, Karali Kaan, Juan Bustamate, Akin Ibrahim, and Kazumasa Orihashi, and covers different aspects of CAVD treatment options, including the recently developed transcatheter aortic valve implantation. Chapter 18, written by Hideaki

This book will provide the most up-to-date knowledge in the fast-growing and ever-chang‐ ing field of aortic valve pathobiology. We hope that it will be useful for cardiologists, cardio‐ vascular surgeons, fellows, and scientists who, we believe, should always be searching for updates in diagnosis, treatment, and research advancement. This open-access book will pro‐

I acknowledge my mentors — Dr. Frederick J. Schoen, for introducing me to the exciting biology of cardiac valve disease, and Dr. Peter Libby, for his continuous support and inspi‐ ration. And I can never thank my family enough — especially my husband, Dr. Masanori

> **Elena Aikawa, MD, PhD** Associate Professor of Medicine

> > Harvard Medical School

Boston, USA

Director, Vascular Biology Program

Brigham and Women's Hospital

Center for Interdisciplinary Cardiovascular Sciences

Senzaki on congenital aortic stenosis in pediatric patients, closes this section.

Aikawa, for believing in me and encouraging me throughout my career.

vide the most current information on CAVD.

X Preface

**Chapter 1**

**Extracellular Matrix Organization, Structure, and**

Heart valves are thin, complex, layered connective tissues that direct blood flow in one di‐ rection through the heart. There are four valves in the heart, located at the entrance to and exit from the ventricular chambers. The normal function of the heart valves is essential to cardiovascular and cardiopulmonary physiology. The opening and closing of valve leaflets at precise times during the cardiac cycles contributes to the generation of sufficiently high pressure to eject blood from the ventricles, and also prevents blood from flowing backwards

The ability of heart valves to open and close repeatedly, as well as the maintenance of the phenotypes of valvular cells, is made possible by their tissue microstructure, specifically the composition and orientation of extracellular matrix (ECM). The ECM within heart valves is primarily comprised of collagen, elastic fibers, and proteoglycans and glycosaminoglycans, although other ECM components are present as well. Taken together, the ECM performs several roles in heart valves. First, the ECM plays a biomechanical role: it is responsible for the unique mechanical behavior of the valve tissue and thus the overall valve function. Sec‐ ond, the valvular cells are bound to and surrounded by the ECM that is located within the immediate vicinity of the cell; this ECM is specifically known as the pericellular matrix (PCM). The PCM influences cell function by serving as a source of ligands for cell surface receptors, which transfers mechanical strains (experienced by the leaflet tissues) to the cells and initiates intracellular signaling pathways. Third, the various types of ECM have differ‐ ent innate mechanical behaviors, for example with collagen being stiffer than elastic fibers,

> © 2013 Wiltz et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

into the heart instead of forward towards the systemic circulation and the lungs.

Dena Wiltz, C. Alexander Arevalos, Liezl R. Balaoing, Alicia A. Blancas, Matthew C. Sapp, Xing Zhang and

Additional information is available at the end of the chapter

**Function**

K. Jane Grande-Allen

http://dx.doi.org/10.5772/52842

**1. Introduction**
