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.
THE PHARMACOLOGIC ERA
The 1980s and 1990s saw the availability of several pharmacologic tools for assessing the roles of the SNS and RAAS in heart failure. The hypotensive effects of angiotensin-converting enzyme (ACE) inhibitors and, later, angiotensin-receptor blockers (ARBs) were sources of concern, since many patients with advanced heart failure had low- to normal-range blood pressures before they received RAAS blockers. However, our group as well as others observed that abrupt blood pressure reduction occurred primarily in patients with very hyperreninemic responses to intravenous diuretics (ie, volume-depleted patients). Eventually, we learned that low baseline blood pressure did not adversely affect outcomes when vasodilators were used in patients with heart failure,18,19 leading us to titrate these drugs upward over days to weeks.
Several different combinations of vasodilators were used successfully to treat heart failure, including hydralazine, isosorbide dinitrate,20 ACE inhibitors,21,22 and ARBs.8,23–28 Direct-acting calcium channel blocking vasodilators, such as amlodipine, did not improve survival in patients with systolic heart failure, although they appeared to be safe in this setting.29 The aldosterone receptor blockers spironolactone30 and eplerenone31 were later demonstrated to improve survival of patients with advanced systolic heart failure when added to vasodilator therapy.
By the end of the 1990s, it was evident that drugs that blocked the SNS and RAAS were not just vasodilators or “afterload reducers,” similar to α-blockers, hydralazine, nitrates, and amlodipine. Neurohormonal blockers were doing something profoundly beneficial not observed with more direct-acting vasodilators.32–37 Simple afterload reduction was not enough in patients with systolic heart failure.
Neurohormonal antagonists were acting more directly on the myocardium. They were preventing the progression of LV remodeling and, in some cases, promoting reverse remodeling, thus improving myocardial function and favorably influencing the natural history of heart failure.31–39 We were astonished to discover that the failing, dilated heart could revert to normal size in response to neurohormone blockade with ACE inhibitors and β-adrenergic blockers; these findings were soon reported by other laboratories as well.
Contrary to our concept of heart failure in the 1970s, we now understood that the heart has inherent plasticity. It can dilate in response to abnormal loading conditions or myocardial injury, and it can restore itself to normal size when neurohormones are blocked and perverse loading conditions are improved. This reversal can occur spontaneously if an offending agent such as chronic alcohol use or inflammation is removed, but it is likely facilitated by SNS and RAAS blockers.
THE REMODELING ERA
Ken McDonald joined the University of Minnesota lab in 1989 as a research fellow. His skill in conducting both animal and clinical mechanistic studies was pivotal to our achieving our research goals. The inspired animal work by Boston-based Marc and Janice Pfeffer revealed the significance of the LV remodeling concept in the development of heart failure36: ventricular remodeling was a hallmark of systolic heart failure, and pharmacologic inhibition of LV remodeling by blocking neurohormones had profound clinical implications.
Under the direction of Wenda Carlyle, a molecular biology laboratory was established at the University of Minnesota whose work was dedicated solely to exploration of remodeling at a very basic level. Alan Hirsch was recruited from Victor Dzau’s laboratory at Brigham and Women’s Hospital in Boston to extend our efforts to understand the molecular basis of cardiac remodeling. Ken McDonald guided the use of magnetic resonance imaging to study remodeling in dogs.
The late 1970s saw the initiation and eventual execution of several important clinical trials, including the Vasodilator Heart Failure Trials (V-HeFT I and V-HeFT II)40,41 under our leadership, and Studies of Left Ventricular Dysfunction (SOLVD)5,6 under the leadership of Salim Yusuf and others at the National Heart Lung and Blood Institute (NHLBI). Many neuro hormonal and remodeling substudies sprang from these large clinical trials. Spencer Kubo joined our group from the Medical College of Cornell University in the mid-1980s, and he immediately demonstrated his prowess in clinical research. He also recruited Alan Bank to study the endothelium in both experimental and human heart failure.
Integrating the molecular, animal, and clinical laboratories allowed us to pursue many mechanistic studies. Laboratory meetings, often held on Saturday mornings, generated ideas for program projects that were subsequently funded by NHLBI. Birthday parties and other social events with laboratory staff and their families were part of our fabric. Late-night trips to the Post Office to send off abstracts for national meetings before the midnight deadline were a regular feature.
Our coordination of and participation in the large clinical trials allowed us to meet frequently in Bethesda with colleagues from other major centers, fostering many collaborations and friendships that continue to thrive. Susan Ziesche deserves much of the credit for coordinating many groups that were part of these large, complex trials. Cheryl Yano, our administrator, also played a key role. All National Institutes of Health (NIH) grants passed through Cheryl, and she worked tirelessly to ensure that the proposals were in the best possible shape before we submitted them. Inder Anand joined our group in the early 1990s and became a major analytical force. Jay Cohn was the intellectual leader of the group, as well as our soul and inspiration. People worked hard for him, and he taught us much in a setting that valued creativity and new ideas above all.
