As a heart fails, losing its ability to squeeze blood through the circulatory system, the body releases a neurohormone that interferes with the heart's best chance to improve contractility, a team of Temple University School of Medicine researchers show in a study published September 9th in the American Heart Association journal, Circulation.
The discovery reveals a promising target for the treatment of end-stage heart failure, and raises intriguing questions about why a drug used to treat some forms of end-stage heart failure improves symptoms but fails to extend lives or reduce hospitalization rates.
"This is a new mechanism that regulates cardiac function acutely," said Douglas G. Tilley, PhD, a pharmacology assistant professor at Temple University. "Its action hasn't really been appreciated before."
Tilley and Arthur M. Feldman, MD, PhD, Executive Dean and Professor of Medicine at Temple's School of Medicine, led the work examining the effect of arginine vasopressin (AVP), which heart failure patients overproduce. It's long been known that the higher a patient's AVP level, the greater the likelihood of death. But no one knew why.
Until now, it was believed vasopressin had two principal roles. It increased blood pressure by narrowing arteries, through its interaction with the vasopressin type 1A receptor, and it induced the kidneys to absorb more water and produce less urine, through the vasopressin type 2 receptor. But vasopressin's direct impact on the heart itself was unknown. "The common belief was that the vasopressin receptor in the heart was just not very important," Feldman said.
When researchers gave vasopressin in animal experiments, they dismissed any observed changes in heart function as a byproduct of vasopressin's action as a vasoconstrictor, which was making the heart work harder, Feldman said. The Temple researchers, by working with ex vivo hearts - that is, hearts removed from the body, with no vasculature - demonstrated that the effect of vasopressin type 1A receptor on cardiac function was independent of its role as a vasoconstrictor. In fact, it was preventing the heart from receiving important signals.
Vasopressin, it turns out, interferes with the body's attempt to rescue a failing heart, Feldman explained. As the heart muscle loses contractility, the body releases catecholamines - the same neurohormones that flood the blood stream in the face of danger. Catecholamines provide the juice for 'fight or flight' and make the heart work harder. Feldman and Tilley's research shows that vasopressin impairs the catecholamine receptors so that the heart never gets the message that would help its flaccid muscles contract more efficiently.
"This makes the heart vasopressin receptor, or some of the downstream signaling, a new and important target for therapies in patients with heart failure," Feldman said. If the V1 receptor could be blocked, or its signal interrupted, catecholamine signals could get through.
The discovery could be of critical importance to end-stage heart failure patients whose kidneys retain too much water, Tilley explained. To stop the kidneys' life-threatening water-retaining excess, these patients receive a drug, usually tolvaptan, that blocks only the vasopressin type 2 receptors in the kidneys. Once V2 receptors are blocked, the kidney stops retaining water. But V2-receptor blockers boost levels of circulating vasopressin throughout the body, including the heart. These elevated vasopressin levels may further interfere with catecholamine signaling in the heart.
"We're concerned that when using a V2R blocker in acute heart-failure patients who already have elevated AVP, you may enhance AVP levels in the heart, dampening contractile reserve, and negatively impacting survival of acute heart-failure patients," Tilley said.
"We think this is an explanation of why V2-selective vasopressin blockers don't really improve survival," Feldman said. "It would suggest what you really need to do is to combine a V1-block with a V2 blocker. We can't say what happens in humans; we haven't looked at that. But if what happens in a mouse model correlates with what goes on in humans, I think it warrants further investigation."
It also may explain the results of a study Feldman analyzed with another V2-blocker, lixivaptan. A partial summary of the results were published in April in Clinical Pharmacology & Therapeutics. In that study, some 400 patients were treated with lixivaptan or a placebo over 60 days. While the drug effectively lessened water retention, it failed to improve survival, cognitive function, and length of hospital stay. Further, more patients died in the treatment arm of the study than died in the placebo arm during the first 10 days of therapy, although the results never reached statistical significance. In all, 15 patients treated with lixivaptan died in the first 10 days, compared to four deaths in the placebo group. An FDA advisory committee reviewing the drug unanimously denied its approval.
"When we saw the trials with tolvaptan, and saw that it improved symptoms but didn't improve survival or hospital length-of-stay, we started to scratch our heads," Feldman said. "First we saw tolvaptan wasn't doing what we expected it to do, then lixivaptan actually caused harm. We thought maybe there is something going on with the vasopressin receptor in the heart that we weren't aware of."
The Circulation paper is the culmination of that work. In it, the researchers looked at the impact of vasopressin type 1 receptors in isolated cardiomyocytes, then in ex vivo hearts, and finally in a mouse model of heart failure.
Also involved in the research are Weizhong Zhu, MD, Valerie D. Myers, MsC, Jianlliang Song, MD, PhD, Constantine D. Troupes, BScH, Ryan C. Coleman, BScH, Larry A. Barr, PhD., Catherine A. Makarewich, PhD, and Steven R. Houser, PhD, from the Temple Cardiovascular Research Center of Temple University School of Medicine; Erhe Gao, MD, Rhonda L. Carter, BS, Laurel A. Grisanti, PhD, Walter J. Koch, PhD, and Joseph Y. Cheung, MD, PhD, from the Center for Translational Medicine at Temple University School of Medicine; Daohai Yu, PhD, Department of Clinical Sciences at Temple University School of Medicine; and Xue Li, MD, from the Division of Cardiology, Fourth Military Medical University, Xian, China.
The work was supported by National Institutes of Health grants HL105414, HL091799, HL074854 and HL033921; a Pennsylvania Health Research Formula Fund (SAP#4100060220); and American Heart Association postdoctoral and predoctoral fellowships.