Cardiac Remodeling: Mechanisms and Treatment PDF

Preface

Over the last several decades there has been a striking increase in the prevalence of heart failure in the United States and other industrialized nations. One of the more astonishing aspects of this pandemic is that it has occurred during a time when the incidence of other major cardiovascular diseases is declining. Although there are several explanations for this paradox (including, most notably, the aging of the population), the one that is perhaps most vexing is that advances in the treatment of coronary disease, myocardial infarction, and valvular heart disease have improved the immediate survival of patients, who are then at increased risk for the future development of heart failure. The major reason for the progression to heart failure in these patients is that the initial injury to the left ventricle initiates a complex series of structural changes throughout the myocardium that ultimately leads to global deterioration in cardiac function. From a genetic and cellular perspective these changes tend to be prototypic in nature, occurring regardless of the nature of the initiating injury. Ultimately, they result in an increase in left ventricle cavity size and muscle mass, deposition of fibrous tissue throughout the myocardium, and changes in chamber configuration. These structural changes are linked to a progressive deterioration in left ventricle systolic and diastolic function. Cardiac remodeling is the ‘‘umbrella'' term that has been most commonly used to describe this complex and multi-faceted process. It stands to reason, then, that defining the causes and mechanisms responsible for cardiac remodeling is essential for understanding the pathogenesis of heart failure. The aim of this book is to provide a comprehensive overview of this process. The various chapters include information that should be helpful to clinicians and researchers alike as they provide insight into the causes, mechanisms, and current (as well as prospective future) treatments of cardiac remodeling.

Over time different paradigms have been used to describe the syndrome of heart failure. During the early part of the latter century and lasting into the 1960s heart failure was perceived to be a cardio-renal syndrome. According to this paradigm heart failure was caused by abnormalities in the pumping function of the heart that resulted in salt and water retention by the kidney. This paradigm was modified over the next decade when it was recognized that the load (or stress) placed on the walls of the heart was an important determinant of function, and that it also produced important changes in cardiac structure. Indeed, the genesis of the concept of cardiac remodeling can be attributed to observations made during this period. The role of the peripheral circulation in modulating wall stress and cardiac structure and function then gave rise to the cardio-circulatory model of heart failure.

As researchers began to study the factors that controlled vascular tone it soon became apparent that neurohormonal systems played an important role in this process. With further study of the renin–angiotensin–aldosterone and sympathetic nervous systems, evidence accumulated that their effects reached well beyond those on the peripheral circulation alone. Angiotensin II, aldosterone, and norepinephrine were recognized as having widespread systemic and cardiac effects that contributed to the pathogenesis of heart failure. One of the most important of these was to promote the growth of cardiac cells, which as it turns out is a fundamental component of cardiac remodeling. These insights gave rise to the neurohormonal paradigm of heart failure, and they have provided a rationale for the testing of neurohormonal antagonists in patients with this condition. Several of these agents have now been found not only to favorably alter the remodeling process but also to favorably alter the clinical course of patients with heart failure. As the neurohormonal paradigm became ascendent, the direct and powerful relationship between cardiac remodeling and the development of heart failure was recognized.

Although there will probably be further insights into the pathogenesis and treatment of heart failure that are based on the neurohormonal paradigm, it is likely that future mechanistic and therapeutic ‘‘breakthroughs'' will come from yet another paradigm. This is the evolving genetic paradigm of heart failure, and it will rely heavily on the insights gained from the study of gene structure and function. Much of the basic work in this area will incorporate techniques of molecular biology to approach problems related to pathophysiology. This paradigm has already provided new insights into the mechanisms responsible for cardiac remodeling, and it has resulted in a variety of useful experimental models for testing emerging therapeutic approaches.

Since the overall aim of the book is to provide a comprehensive description of cardiac remodeling, the reader will note that the authors of the various chapters in this book will alternate between the four paradigms of heart failure that are described above. The reason for this is that, while all are helpful, none, by themselves, are entirely sufficient to account for the complex series of changes that take place as the heart remodels.

The initial section of the text is focused on the pathophysiology of cardiac remodeling and the mechanisms involved in the deleterious changes in cardiac structure that ultimately result in heart failure. This section is introduced by a chapter contributed by Dr. Jay Cohn, one of the first clinicians/scientists to recognize the importance of remodeling in the pathogenesis of heart failure. It is followed by chapters describing the molecular, cellular, tissue, and organ changes that occur as the heart remodels. In addition, there are detailed descriptions of the model systems that have been developed to further study the remodeling process and the effects of various interventions aimed at halting or reversing it. This segues nicely into a series of chapters dealing with the causes of remodeling and, in particular, the critical role played by neurohormonal activation in the pathogenesis of this process. The clinical aspects of remodeling, including information about natural history, detection, and treatment options, then follow. One of the most exciting aspects of clinical cardiology to emerge over the last several decades is the recognition that therapeutic interventions can inhibit and sometimes even reverse the remodeling process. Chapters outlining the role of medical and surgical therapies and the emerging role of devices in treating remodeling and heart failure are included, and there is a final chapter describing the future prospects for the treatment of cardiac remodeling.

The importance of understanding and treating myocardial remodeling has never been greater, considering the societal impact of heart failure throughout the industrialized world. Given the intimate connection between progressive cardiac remodeling and deterioration in cardiac function, it is essential that we more effectively recognize and treat this process. This goal takes on added urgency since it is anticipated that there will be a doubling in the heart failure population over the next three to four decades.