Vascular Mechanics and Pathology Mano J. Thubrikar Vascular Mechanics and Pathology Mano J. Thubrikar, Ph.D., FAHA Formerly, Research Associate Professor of Surgery, University of Virginia Health Sciences Center, Charlottesville, VA Associate Director, Heineman Medical Research Center, Carolinas Medical Center, Charlotte, NC Adjunct Professor, Dept. of Mechanical Engineering, University of North Carolina at Charlotte, NC Currently, Edwards Distinguished Research Scientist, Edwards Lifesciences, Irvine, CA Library of Congress Control Number: 2006925108 ISBN-10: 0-387-33816-0 e-ISBN-10: 0-387-68234-1 ISBN-13: 978-0-387-33816-3 e-ISBN-13: 978-0-387-68234-1 Printed on acid-free paper. ©2007 Springer Science+Business Media, LLC All rights reserved. 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The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject to proprietary rights. 9 8 7 6 5 4 3 2 1 springer.com Dedicated to my family— wife Sudha, daughter Vaishalee, son Vishal, father Jumdeoji, and mother Varanasi It is the basic principle—in science—which says: “All things being equal the simplest explanation is the right one.” —William of Ockham Preface Nowhere in the scientific progress has the schism in the knowledge been as striking as in the case of vascular mechanics and pathology. This joint subject would serve as a classic example of science developed in two different directions. It provided the motivation to put forth this book and establish a correlation between vascular mechanics and pathology. The book focuses on the artery and arterial diseases. The most fundamental functions of the artery are (1) to serve as a conduit of blood flow and (2) to serve as a container of blood pressure. The artery carries the blood to all organs of the body and it uses pressure to drive the blood through the tissue to provide nourishment. Hence, the artery is both a pipe and a pressure vessel. The artery pulsates about 103,000 times a day along with the beating heart. In a lifetime, the artery sustains cyclic pressure for about 3.8 billion cycles. This obviously poses a significant challenge to the artery and therefore the artery must be endowed with special structure and properties to meet this challenge. In the event that additional challenges are imposed, such as high blood pressure, it would not be surprising that the artery could “break down” or become diseased. In the book, we examine the structure and properties of the artery and study the challenges imposed on it with a view to understand the survival of and the development of the diseases in the artery. Two separate bodies of knowledge have developed in great detail, which are of interest to us. They are (1) arterial diseases, particularly atherosclerosis and aneurysm and (2) engineering analysis of pressure vessels. In arterial diseases, the most common is atherosclerotic plaque, which predominantly forms at branches, bifurcations, and curvatures. The second most common is the aneurysm, which, among other locations, also forms at the branches of cerebral vessels. Other situ- ations concerning the artery are hypertension, use of beta-blockers to reduce the heart rate, exercise which increases and then reduces heart rate, aortic dissection, orientation of cells, and balloon angioplasty. Development of hyperplasia or aneurysm at the arterial anastomosis is also an interesting example. Why do we use veins from the lower leg for coronary artery bypass grafts is not obvious to many. These are some of the topics that need explanations and the book addresses them in terms of vascular mechanics. vii viii Preface The other body of information exists in the field of pressure vessel engineer- ing. For mechanical engineers pressure vessels are the means by which outer space and ocean depths are reached, nuclear power harnessed, energy systems controlled, and petroleum processes operated. The demand for high pressure and large diameter vessels has been accompanied also by a demand for weight reduc- tion and structure fabrication, posing a challenge for design engineers. In the body, nature has taken on a challenge for making the most efficient structures that will achieve storage, compliance, and flexibility all at once. In pressure vessels, it is recognized that the vessels fail from fatigue in locations where stress con- centration occurs. The stress concentration occurs in localized regions of vessel intersections, bifurcations, curvatures, and holes. The pressure vessels are rein- forced by such means as increased thickness and use of stronger materials. For the mechanical pressure vessels, the design engineers can consider pres- sure as the direct cause of rupture or failure, but for the artery, a living biological material, pressure alone can seldom be considered a cause of the disease. Cellular, biochemical, genetic, and other biological processes will be intimately involved, and a mechanical entity, such as pressure, may have its consequences either directly or through these pathways. For physicians, high blood pressure in patients sends alarming signals that put all on alert, from blowout of an aneurysm in the aorta, from blowout of an aorta due to dissecting aneurysm, from blowout of a berry aneurysm in the cranium, from enhancement of atherosclerotic disease, exhaustion of the heart working harder against the pressure, and alike. When one acquires the knowledge of these two fields, the similarity between the failure of pressure vessels and the occurrence of arterial diseases is inescapable and this book serves to point that out. It is known that the heart muscle becomes thicker in aortic stenosis and the heart chamber volume becomes larger in aortic insufficiency; both conditions are indicative of a cause and an adaptive response. It is also known that arteries become thicker in hypertension. These correlative relationships, however, have not been extended previously to the most important and pervasive diseases of the artery. The book explains that the parameters that determine the mechanical failure of the pressure vessels are also the ones that mat- ter the most in the “failure” of the blood vessels and that the failure appears in the form of atherosclerosis or aneurysm. The book begins with the description of previously reported mechanisms of atherosclerosis and aneurysm, and points out why these mechanisms appear incomplete. It then describes the structure of the artery and how it is suited to the dual function of the artery. For the first time, it describes the structure of the arterial branch. The principles of pressure vessels are then described and applied to the coronary arteries, carotid bifurcations, aortic bifurcations, aortic arch, etc. Both the general principles and the occurrence of stress concentration at the pres- sure vessel junctions are described. The orientation of endothelial cells and smooth muscle cells, and higher permeability of specific regions of the artery to low density lipoprotein are described. The proliferation of cells in balloon angio- plasty as a response to strain is described. The reduction of stress and the role of beta-blockers in the reduction of atherosclerosis and/or related complications are Preface ix described. The principles of reinforcements and reduction of diseases are applied to intramyocardial coronary arteries and vertebral arteries. The book describes the use of veins as the arterial grafts and the role of vein valve in graft stenosis. The principles of stress concentration are further illustrated in case of anasto- mosis. The development of intimal hyperplasia at the anastomosis and the devel- opment of anastomotic aneurysms are covered once again from the point of view of vascular mechanics. The intracranial aneurysms and the aortic aneurysms are described with emphasis on the stress in the aortic wall. Aneurysm formation, growth, and rupture are described using pressure vessel principles. Finally, the aortic dissection is described and, for the first time, it is shown that the aortic root mechanics plays a very important role in the development of this pathology. Both pulling and twisting motions of the aortic root are analyzed for their role in the aortic dissection. Overall, the two fields of science are brought together to enrich our under- standing of the role of vascular mechanics in pathology. A broad range of subjects covered in the book provides one of the most comprehensive treatments of vascu- lar pathology in a single document and makes this document four books in one. It enhances our knowledge of both engineering and medicine by pointing out the important link between them in the area of vascular pathology. It also promotes understanding of a common phenomenon in such varied subjects as atherosclero- sis, aneurysms, pressure vessel, stress concentration, vein grafts, anastomosis, cell proliferation, and beta-blocker treatment, all associated with arterial diseases. It points to newer applications of engineering principles in medicine thereby open- ing new avenues for experimental research in both the fields. Usually, it is the philosophers’ forte to try to understand “all things in terms of a single principle” but serendipitously, in this book, it is “the single principle” that has been brought to the forefront of multiple vascular diseases. The book will be useful to cardiovascular surgeons, cardiologists, pathologists, radiologists, neurosurgeons, anatomists, and manufacturers of medical devices. It will also be useful to students in medicine and in biomedical engineering and to the researchers in various disciplines. It can serve as “the book” for a course on “vascular mechanics and pathology” in bioengineering. It is likely to open new doors for interdisciplinary research, which could lead to the reduction of vascu- lar diseases and to the development of new treatments, thereby benefiting large number of patients. Irvine, California, USA Mano J. Thubrikar, Ph.D., FAHA Acknowledgments Writing this book was a big task and a significant challenge because it is based on almost twenty years of laboratory research while I was at the Department of Surgery, University of Virginia, Charlottesville, Virginia, and at the Heineman Medical Research Center, at Carolinas Medical Center, Charlotte, North Carolina. The work included in the book came from the following collaborations: At the University of Virginia, in the Health Sciences Center, collaborations with the Departments of Anatomy and Cell Biology, Biochemistry, Physiology, and Pharmacology; in the School of Engineering, collaborations with the Departments of Civil Engineering and Applied Mechanics, and Biomedical Engineering; collab- orations with AB Hassle Pharmaceutical Company, Gothenberg, Sweden; at the University of North Carolina at Charlotte, collaborations with the Department of Mechanical Engineering; and at the Carolinas Medical Center, Charlotte, collabo- rations with Sanger Surgery. This comprehensive book would not have been possi- ble without such broad collaborations and indeed because of that it has far-reaching implications. There are special reasons to acknowledge certain people without whom the work, and therefore the book, would not have been possible. They are Dr. Stanton P. Nolan, Dr. J. David Deck, Dr. Richard T. Eppink, and Dr. Bengt Ablad. The work and the book are primarily based on the principles of mechanics applied to the arterial pathology, particularly atherosclerosis and aneurysm. The work was begun at a time when there was no support for such an approach and, in fact, there was resistance to pursuing these studies. At such a time one person, Dr. Stanton P. Nolanfrom the Department of Surgery, University of Virginia, was instrumen- tal in supporting, encouraging, and participating in this approach. My sincere and special thanks go to him for being the enabler. Drs. Deck and Eppink soon joined, and the team was formed. Dr. Bengt Ablad(AB Hassle Pharmaceutical Co.) was also a key person for financially supporting the projects for several years as he saw the value of this approach in understanding the actions of beta-blockers. Subsequently, Dr. Francis Robicsekof the Carolinas Medical Center supported and participated in this work, thereby enhancing it significantly. My very special thanks go to him. There are others who were quite instrumental in encouraging this work. They are Dr. Peter Holloway (UVA), Dr. D. Kenyon, Dr. Russell Ross xi xii Acknowledgments (editor of Arteriosclerosis), Dr. Seymore Glagov (University of Chicago), Dr. Gardner McMillan (NIH), Dr. Y.C. Fung (UC San Diego) and Dr. Thomas Clarkson (Wake Forest University). These individuals played a determining role in my pursuit of this approach and I am truly indebted to them. There were several individuals who participated in the experiments described in the book. I thank all of them. Among them Dr. Radha Moorthy, Dr. Michel Labrosse, and Brett Fowler contributed significantly. Typing of the entire manuscript was done by Brigitte Dorn, and I cannot thank her enough for her tremendous efforts. My thanks also go to Dr. Chun-An Lin and Harold Rice for their invaluable help with the figures. Lastly, and most importantly, my thanks and gratitude go to my wife, Sudha Thubrikar, whose patience, understanding, and support for five years, during the writing of this book, was exemplary and humbling. The book would not have been possible without her help. Yorba Linda, California, USA Mano J. Thubrikar