Renin Angiotensin System and the Heart
Walmor C. De Mello, ed.
256 pp. New York, NY: John Wiley & Sons; 2004. $167.00. ISBN 0-470-86292-0
More than a century ago, Tigerstedt and Bergman identified an extract of the rabbit kidney, renin, which when administered intravenously, produced a sustained elevation of blood pressure. Harry Goldblatt, a half-century later, rekindled interest in renin in a series of brilliant physiological experiments demonstrating that diminished renal blood flow (and pressure) generated a powerful renal pressor response. Over the next 30 years, Page, Braun-Menedez, and others delineated what has come to be called the “classic” or systemic renin-angiotensin system (RAS). In a circular feedback loop, renin, secreted by the kidney in response to volume and pressure changes, intravascularly transforms angiotensinogen, generated in the liver, to angiotensin I. This, in turn, is catalyzed to angiotensin II (AII)—the “business end” of the RAS cascade—by endothelium-bound converting enzyme (ACE). AII modulates pressure through vasoconstriction and sodium retention. This rapid response system is now recognized to be one, albeit an important one, of many competing and redundant neurohormonal systems that together maintain hemodynamic integrity. The individual components of the RAS have been successful targets for pharmacological interventions that have both confirmed the physiological role of the RAS and become mainstays of modern management of hypertension.
More recently, the RAS has been shown to demonstrate a variety of cellular effects, in addition to the hemodynamic functions mentioned above. By inducing cellular hypertrophy and proliferation and stimulating protein generation, the RAS influences organ structure and function. These effects are independent of RAS-related hemodynamic changes. AII also has been implicated in endothelial dysfunction, production of reactive oxygen species, inflammation, stimulation of hemostasis, and insulin resistance. In the heart, RAS stimulates cardiomyocyte hypertrophy and fibroblast proliferation that leads to left ventricular hypertrophy, diastolic and systolic dysfunction, arrhythmia, heart failure, and, ultimately, cardiac death. These AII effects are subject to inhibition by the same agents that block the systemic RAS.
During the past decade, substantial evidence has emerged to support the presence of a self-sufficient RAS, tissue RAS (tRAS), that is capable of producing these cellular and subcellular effects within the heart. tRAS appears to exist parallel to and independent of the systemic RAS. To bring together evidence that explains the cardiac tRAS, De Mello has assembled a multiauthored volume containing brief reviews of the several streams of research that have contributed to our current understanding of cardiac RAS. De Mello contends that a more precise and detailed exposition of the workings of the tRAS may provide the “real physiological meaning of the cardiac renin angiotensin system.”
The individual chapters present the results of different investigative strategies designed to identify RAS components and their functions at the cellular level. Thus, a clear review of the transgenic animal model approach provides data to support the local expression of the RAS components in the heart and their capability, independent of the systemic RAS, to have direct mitogenic, growth, and apoptotic effects in the heart. Other investigators use in vitro tissue and cell systems to explore the place and function of the local RAS. The nearly uniform conclusion is that every molecular component of the system does exist in the heart, but they may not be produced there. Instead, the components may be recruited from the circulation. The net result can be a relatively high concentration of AII proximal to its cardiac receptors. The source of cardiac renin is particularly contentious. Renin has not been identified in anephric humans, but it is possible that there are differences among species, and, as noted in the chapter by Jörg Peters, there may be different renin transcripts from the same gene that have different expression. This could explain the finding that renin is produced locally in some animal models. The presence of different renin transcripts also holds open the possibility of functionally different renin systems within the heart. In the end, virtually all of the authors concede that the importation of extracardiac renin (or prorenin, or both) probably accounts for most if not all cardiac renin. The existence of both AT1 and AT2 receptors suggests differing activities of AII that may be complimentary or competitive, but the data in De Mello’s book suggest that the specific role of the AT2 receptor remains elusive.
Taken together, these brief chapters provide powerful evidence that a local RAS is capable, in response to either ischemic or stretch injury, of causing cardiac hypertrophy, increased oxygen demand, increased intercellular collagen, enhanced arrhythmia, reduced coronary reserve, myocardial infarction, congestive heart failure, and finally, cardiac death. These phenomena have been observed independent of the systemic RAS and can be muted by blockade of ACE, the AT1 receptor, or both.
The multifaceted capacities demonstrated in this book suggest the possibility of both a physiological and pathological role for tRAS in the heart. For example, the response to coronary artery occlusion is characterized by the growth of cardiomyocytes and the proliferation of collagen-secreting fibroblasts. One might conclude, perhaps naïvely, that this initial reparative response to ischemia might be protective. Apparently, that is not the case because immediate blockade of the RAS in the acute myocardial infarction setting has proved to be clinically valuable.
The clarity with which it has been possible to implicate tRAS with the downward spiral from hypertension through cardiac hypertrophy, electrical instability, and muscular dysfunction to heart failure in a way highlights both what is known and unknown in the field. Although the individual system components’ actions are well displayed in the book, their interaction and larger context remain mysterious. Varagic and Frohlich try to describe how these 2 systems might interact in the clinical setting. They suggest that the classic system is attuned to the immediate hemodynamic situation, whereas the tRAS carries structural and functional responsibility at the cellular level. One could simply interpret that to mean that these are physiological and pathological dimensions of 1 system. Unfortunately, they are unable to shed much light on how the systemic and tissue systems interact.
Other fundamental issues exist for which illuminating data are unavailable: Do stimuli, which ignite the renal renin response, also activate the cardiac system? Does pharmacological interruption of the systemic RAS similarly affect the local system? Is there a physiological role for the cardiac RAS, and does the AT2 contribute? Does the RAS play a role in atherosclerosis, and, if not, why does activity of the RAS predict myocardial infarction independent of blood pressure in patients with hypertension? That these questions exist does not imply a shortcoming of the book but instead attests to the salience of the splendid research assembled by De Mello.
Finally, one cannot avoid wondering why the compelling evidence of the adverse effects of a cardiac RAS has not been reflected by more impressive cardioprotection through its blockade. After reading this book, it is surprising that despite clear evidence that RAS blockade can blunt intermediate effects, clinical trials have not uniformly demonstrated a hemodynamically independent cardioprotective effect, particularly in antihypertensive trials in which a strong case can be made that the benefit of treatment has been dependent on falling blood pressure. In these trials, the only outcome that is not blood pressure-dependent is heart failure, and, of course, it is the progression to heart failure that is most closely linked to tRAS. No simple explanations can be found for these clinical findings, but perhaps systemic blood pressure response is not an adequate surrogate for the cardiac tRAS response. Thus, tRAS may be another independent source of heterogeneity and another mystery to unravel before optimal cardioprotective therapy can be devised for each individual.
It is always a challenge to collect and publish independently authored chapters that address a single topic. Because different research strategies addressed similar issues, an overall summary chapter or more cross-referencing (or both) would have been welcome. Despite some inevitable overlap and redundancy, De Mello has achieved considerable coherence by imposing both brevity and organizational uniformity, coupled with a heavy emphasis on an adequate set of references. Students, clinicians, and clinical investigators engaged in cardiovascular disease treatment or study are likely to find this book an excellent place to begin a study of or to review what is known about the cardiac RAS.