A new study reveals the mechanism responsible for a rare but potentially devastating form of heart failure that sometimes afflicts women late in pregnancy or shortly following childbirth, researchers have reported in the Feb. 9, 2007 issue of Cell, a publication of Cell Press. The so-called postpartum cardiomyopathy (PPCM)--which is estimated to complicate one in every 1,300 to 4,000 deliveries in the U.S. --is considered among the leading causes of death among postpartum women in industrialized countries.
The researchers discovered that mice whose hearts lack a gene that enlists the activities of critical antioxidants develop PPCM. Under those stressful conditions, the mice develop increased levels of another enzyme that cleaves the nursing hormone prolactin, forming an aberrant protein that damages heart muscle. As evidence that the findings in animals hold for humans, the researchers found a similar imbalance of proteins in the cardiac tissue of PPCM patients.
Moreover, the report finds, both in mice and in a small number of patients at high risk for PPCM, that the prolactin-blocking drug bromocriptine might reverse or prevent the often fatal cardiac disorder. The drug is already known to be a safe method for inhibiting prolactin in women who wish to halt milk production, the researchers said.
"This disease, while rare, can be very traumatic," said Helmut Drexler of Medizinische Hochschule in Hannover, Germany. "Survival can be very poor and some who survive require a heart transplant."
"Nobody knew why women develop this," he said. "We've identified a mechanism and, more importantly, based on our findings, a potentially very effective means to prevent the disease."
Physicians had previously treated women with PPCM with the same heart drugs, including beta blockers and ACE inhibitors, that are traditionally prescribed for any patient with heart failure, he said.
"In all the women who have received the bromocriptine treatment, it has worked," added Denise Hilfiker-Kleiner, also at MH-Hannover. "It has prevented them from getting the disease again."
The women treated were study collaborator Karen Sliwa's patients in South Africa who had already developed PPCM with a previous pregnancy, she said. Women who develop PPCM and survive are at increased risk for developing the condition should they become pregnant again. If they do, they have an approximately 50 percent chance of dying, Hilfiker-Kleiner said.
If our early results are solidified in a larger clinical trial, "this drug could really make an immediate difference," she added.
The researchers found that mice lacking the gene STAT3 specifically in heart muscle cells consistently develop PPCM after giving birth. Indeed, two-thirds of STAT3-deficient mice died after delivering their second litters. STAT3 is involved in protection of the heart from oxidative stress by increasing the levels of antioxidant enzymes. STAT3's role is particularly critical immediately following and in late pregnancy, when oxidative stress is generally high, Hilfiker-Kleiner said.
"On the whole, the oxidative stress may protect against infection," she said. "But at the same time, sensitive organs like the heart need powerful antioxidants. STAT3 is part of that defense mechanism."
Without STAT3, the mice exhibited obvious signs of heart failure as cardiac cells became oxygen deprived and died. Those symptoms were linked to an increase in the enzyme cathepsin D, which clips prolactin hormone to a shorter form that blocks blood vessel formation and causes cell death.
"The 16 kDa prolactin is a powerful destroyer of endothelium and has even been considered as a cancer drug capable of destroying tumors' blood vessels," Hilfilker-Kleiner said. Endothelium is the thin layer of cells that lines blood vessel walls.
"The destruction of endothelial cells in the heart essentially lowers the blood supply," she said.
To confirm the role of the altered form of prolactin in producing heart failure, the researchers treated mice with bromocriptine, a drug that blocks release of the hormone. Mutant mice treated with the drug all survived two pregnancies, while 70 percent of untreated mutant mice died. Bromocriptine treatment also preserved blood vessel formation and cardiac function in animals lacking STAT3.
The research team further found that the hearts of five patients requiring an organ transplant due to PPCM showed reduced STAT3 protein levels compared to normal. Blood tests also revealed that lactating women with PPCM showed signs of high oxidative stress and elevated cathepsin D levels compared to healthy mothers. Mothers with PPCM also had high levels of the 16 kDa prolactin, a form of the hormone that is normally barely detectable.
As a preliminary clinical trial, the researchers treated six women at high risk for PPCM with bromocriptine in addition to standard therapy up to 3 months post-delivery while six high-risk patients received standard treatment. As expected, prolactin returned to non-pregnant levels within two weeks in patients receiving the drug.
Three months after childbirth, all six bromocriptine-treated women had preserved or increased heart function and all survived the 4 month observation period. In contrast, in the group not treated with the drug, three women had died within 4 months.
"Based on our experimental and initial clinical findings, bromocriptine may represent a novel therapeutic option to treat patients with PPCM or to prevent the disease in patients who suffered and recovered from PPCM in a previous pregnancy," the researchers concluded.
The researchers include Denise Hilfiker-Kleiner, Karol Kaminski, Edith Podewski, Tomasz Bonda, Arnd Schaefer, Anja Quint, Ulf Landmesser, Carola Doerries, Maren Luchtefeld, Nils H. Zschemisch, Gunnar Klein, Andres Hilfiker, and Helmut Drexler of MHH in Hannover, Germany; Karen Sliwa and Olaf Forster of Chris-Hani-Baragwanath Hospital, University of the Witwatersrand in Soweto, South Africa; Valeria Poli of University of Turin in Turin, Italy; Michael D. Schneider of Baylor College of Medicine in Houston, TX; Jean-Luc Balligand and Fanny Desjardins of University of Louvain Medical School in Brussels, Belgium; Aftab Ansari of Emory University in Atlanta, GA; Ingrid Struman and Ngoc Q.N. Nguyen of Université de Liege in Sart Tilman, Belgium; Gerd Heusch and Rainer Schulz of Universitaetsklinikum, Essen in Essen, Germany.
This study was supported by the Jean Leducq Foundation, the Deutsche Forschungsgemeinschaft, Deutscher Akademischer Austausch Dienst, and the Foundation for Polish Science.
Hilfiker-Kleiner et al.: "A Cathepsin D-Cleaved 16 kDa Form of Prolactin Mediates Postpartum Cardiomyopathy." Publishing in Cell, 9 February 2007. DOI 10.1016/j.cell.2006.12.036. http://www.cell.com
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