Neurohormonal control of heart failure
ABSTRACT
For nearly three decades, starting in the early 1970s, the cardiology research laboratories at the University of Minnesota served as the focal point for the discovery and implementation of much of the information we now apply to the management of heart failure. Director Jay Cohn, building on his expertise in hypertension and hemodynamics, led many creative and committed investigators in the exploration of the mechanisms responsible for increased sensitivity to afterload in heart failure. The neurohormonal hypothesis of heart failure led to the development of several pharmacologic tools, such as angiotensin-converting enzyme inhibitors, β-adrenergic blockers, and, later, angiotensin-receptor blockers. By the late 1990s, it was understood that neurohormonal antagonists could prevent the progression of left ventricular remodeling and favorably influence the natural history of heart failure. Neurohormonal blockers are now considered standard therapy. Issues remain to be addressed, including early identification and treatment of patients at risk.
We have known for more than 100 years that heart failure is characterized by excessive sympathetic nervous system (SNS) activity. Thanks to refinement of this concept in the 1980s and 1990s, we now have a good understanding of SNS activity in both experimental and clinical heart failure. During those two decades, we also realized the pathophysiologic importance of the renin-angiotensin-aldosterone system (RAAS) in patients with heart failure.1 By 2000, it was obvious that heart failure was inextricably intertwined with excessive neurohormonal activity.2,3 This understanding of the pathophysiology of heart failure took on greater importance with the ability to pharmacologically block these neurohormonal systems, thereby demonstrating the detrimental role of neurohormones in the onset and progression of heart failure.
This article is a brief historical and personal description of the study of neurohormonal control mechanisms as they relate to the clinical syndrome of heart failure. The article includes a personal account of how the story unfolded in the cardiology research laboratories at the University of Minnesota.
THE EARLY YEARS: NEUROHORMONAL HYPOTHESIS
A hypothesis emerged gradually in the 1980s suggesting that progression of heart failure was in part a product of excessive SNS and RAAS activity. Many believed that pharmacologic inhibition of these systems might mitigate against progressive cardiac remodeling and thereby reduce symptoms and extend life—the so called neurohormonal hypothesis.4 SNS blockers and RAAS blockers are now widely used in tandem as first-line therapy to treat patients with heart failure,5–11 but in 1980 we were just beginning to consider their therapeutic effects.
This major shift in thinking about neurohormonal systems and heart failure did not come about quickly. Early success was driven by the ability to quickly and precisely measure neurohormones in the laboratory coupled with the availability of drugs specifically designed to block the SNS and RAAS. It was also critically important to embrace the power of randomized controlled trials to test new therapies. Investigators, research nurses, and patients from many medical centers and laboratories should be credited with this astonishing success. I am proud to have been a part of this activity at the University of Minnesota.
THE COHN LABORATORY
Early work done in the 1960s by numerous investigators noted that the failing left ventricle (LV) was exquisitely sensitive to afterload conditions.12–15 John Ross and Eugene Braunwald explored this observation in patients in 1964.15 Jay Cohn, with his unique background in hypertension and hemodynamics, brought the concept back into the laboratory in the early 1970s, where he explored the mechanisms responsible for increased sensitivity to afterload in patients with heart failure.16
I had the good fortune to join Cohn’s laboratory in 1979, when this avenue of heart failure research was in full bloom. A team of investigators was gradually assembled that included Maria Teresa Olivari, who relocated from the Cardiovascular Research Institute in Milan, Italy, directed by Maurizio D. Guazzi. Also joining the group were T. Barry Levine from the University of Michigan, Ann Arbor; Steven Goldsmith from Ohio State University, Columbus; Susan Ziesche from the Minneapolis Veterans Affairs (VA) Medical Center; Thomas Rector, an expert statistician and pharmacologist at the University of Minnesota; and many research fellows, visitors, students, biochemists, statisticians, and research nurses. Joseph Franciosa joined the University of Minnesota group in 1974 and, after completing several important trials, left in 1979 to lead the cardiology group at the Philadelphia VA Medical Center.
The Cohn group developed a working hypothesis that activation of the SNS and RAAS in heart failure was most likely an adaptive mechanism intended for short-term circulatory support, such as in the setting of blood loss, dehydration, shock, volume depletion, or flight response. In patients with heart failure, according to the hypothesis, the SNS and RAAS activity persisted beyond that needed for adaptation, with chronic release of norepinephrine (NE), renin, angiotensin II, aldosterone, and other neurohormones. The neurohormones ultimately became “maladaptive.” Thanks to the assaying skills of Ada Simon, we had the early advantage of precise and rapid radioenzyme measurement of plasma norepinephrine and renin activity in the blood of patients and animals.
We believed that neurohormonal activation contributed in part to the excessive afterload conditions observed in heart failure. We also thought that excessive neurohormonal activation directly impaired cardiac systolic function. The obvious next step was to explore whether neurohormonal antagonists would improve myocardial performance.
Under the leadership of Steven Goldsmith, many studies were performed to investigate reflex control mechanisms and their pathogenic role in patients with heart failure. The accumulating data suggested that persistent, excessive neurohormonal activity was characteristic of heart failure and that it was associated with a poor prognosis.17 The precise mechanism that drives activation of the SNS remained elusive, however, and is poorly defined even today. In that era, when β-adrenergic blockers were believed to be contraindicated, we inhibited the central SNS with bromocriptine, clonidine, and guanfacine with modestly favorable responses. We inhibited circulating arginine vasopressin antibody (thanks to Prof. Alan Cowley for noting an acute favorable response).
