Today researchers from Germany reported (subscription required) in the Journal of the American College of Cardiology that stopping lactation with bromocriptine, a direct inhibitor of prolactin, facilitated the resolution of peri-partum cardiomyopathy in two patients.
Peri-partum cardiomyopathy has been a heretofore poorly understood disease that causes a diffuse weakening of the heart in woman that develops within the last month of pregnancy or within five months immediately following pregnancy. It carries with it a high degree of mortality in women afflicted with the disease from heart failure or sudden death.
Today's report offers a unique insight as to a possible mechanism for the cardiomyopathy:
Prolactin exists in at least 2 biologically active forms with opposing effects. The physiological full-length 23 kDa prolactin promotes angiogenesis and protects endothelial cells whereas the cleaved 16 kDa derivate induces endothelial cell apoptosis and disrupts capillary structures. Recent data showed that oxidative stress promotes the postpartum generation of 16 kDa prolactin, which is causally related to PPCM. In turn, prolactin blockade with bromocriptine was successful in preventing onset of PPCM in mice and in patients at high risk for the disease.Translating this: a shorter-than-normal piece of the prolcatin molecule is thought to lead to cell death and disrupts tiny blood vessels, possibly leading to the reduced heart function seen in peripartum cardiomyopathy (PPCM). Production of the specific form of dangerous prolactin (16 kDa) can be blocked with administration of bromocriptine in mice, so it was used in two cases in women and appeared to have beneficial effects, restoring heart muscle function in each of them.
The authors admit that the women were also receiving treatment with more conventional beta blocker and angiotensin converting enzyme inhibitors and these may have been responsible for the two patient's recovery, and that some patients recover despite any therapy. But the elucidation of the potential role of prolactin in the pathophysiology of this disease sheds light on a potentially exciting area to be evaluated in a prospective, multicenter trial.
Reference: Denise Hilfiker-Kleiner, PhD, Gerd Peter Meyer, MD, Elisabeth Schieffer, MD, Britta Goldmann, MD, Edith Podewski, MD, Ingrid Struman, PhD, Philipp Fischer, MD and Helmut Drexler, MD. "Recovery From Postpartum Cardiomyopathy in 2 Patients by Blocking Prolactin Release With Bromocriptine," J Am Coll Cardiol, 2007; 50:2354-2355, doi:10.1016/j.jacc.2007.10.006
DA antagonists such as domperidone and metaclopromide are used for increasing prolactin levels to enhance breastfeeding. What do you think of a study that investigates a correlation of PPCM and women who have had their prolactin levels pharmacologically increased? (This would really only consider at the post-partum women though). Anyway, the idea popped in my head as I read this post.
I think this first came out in Cell Magazine in February 2007. http://www.cell.com/content/article/abstract?uid=PIIS0092867407000608
Dr. James Fett wrote that he urged caution on the above information. On August 1, 2007 he wrote on the PPCM support site http://www.amothersheart.org/members :
"I urge caution on this. That is a research study by the group in South Africa and Germany, and I have been close to the South African group, in fact have published papers as co-author with them. That work was done with a genetically-engineered mouse that develops postpartum cardiomyopathy. Here is a copy of my comments to the editorial associated with the article:
Dear Dr. Leinwand,
I urge caution in interpreting the findings of Hilfiker-Kleiner and colleagues reported in Feb 9, 2007 CELL [128:589-600]. The title might better read " A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy in ‘ knock-out’ mice.”
In the CELL report the subject mice developed cardiomyopathy after the introduction of" adenoviral vectors expressing human 16 kDa Prolactin" into the hearts of mice. That is a very long step from the development of PPCM in the human female. Your Leading Edge Preview did not mention this; but appropriately indicated the need for further studies.
It is also probably premature to highlight the potential therapeutic benefit of bromocriptinie (an inhibitor of prolactin secretion) in human subjects with previous diagnosis of PPCM and subsequent pregnancy. In your remarks you identify the potential hazard in stating, "...it would only be administered for a short period of time and therefore may not affect long-term health." At this point in time we are just not sure of that. I believe that we need additional safety studies to first be documented before use of bromocriptine in humans; and particularly because prolactiin is such an important hormone in reproductive health.
Furthermore, we are finding that for women who have experienced recovery of systolic heart function after a diagnosis of PPCM, there is a relatively low relapse rate in the next subsequent pregnancy. If the randomized clinical trial were to be applied as described to these women more than half ofthem would be exposed to a drug of questionable safety who would never have relapsed without the drug anyway. Any results coming out of such a non-discriminatory application of an experimental treatment would therefor be quite suspect.
The improved outcomes in subsequent pregnancy in USA and Haiti have been documenterd by Elkayam [N Eng J Med 2001 ;344:1567-71] and myself [Ann Intern Med 2006; 145:30-34]. I am not sure why Sliwa et al [Am J Cardiol 2004;93:1441-3] showed such poor outcomes in early studies; but I believe that subsequent observations in Soweto have also recorded more PPCM patients who did not relapse with a subsequent pregnancy (personal communications).
As I read the CELL article I find many speculations about biopathologies as well as many interesting and important possibilities for future studies; but I also see the need not to overstate the importance of this report. PPCM is like a 1000-piece jigsaw puzzle and we must carefully and fully scrutinize each piece if we want to see the full picture emerge.
With best wishes, and thanks,
James D. Fett, MD"
Thank you for taking the time to write about PPCM. There is SO MUCH misinformation out there that I feel compelled to share Dr. Fett's comments.
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