Getting around peripartum cardiomyopathy

Michael J. Haas
2012 Science-Business eXchange  
A Harvard Medical School-led team has shown that a soluble form of VEGF receptor 1 causes about one-third of peripartum cardiomyopathy cases-those associated with pre-eclampsia. 1 Ongoing studies are seeking to identify small molecule inhibitors of the protein and determine whether the mechanism also underlies the other two-thirds of cases. Peripartum cardiomyopathy (PPCM) is a form of heart failure that affects about 1 in 1,000 peripartum women. The disease is usually diagnosed a few weeks
more » ... sed a few weeks postpartum, and current treatments are limited to standard therapies for heart failure such as b-blockers and angiotensin-converting enzyme (ACE) inhibitors. A known risk factor for PPCM is preeclampsia, a condition involving hypertension and proteinuria that occurs in about 5% of all pregnant women but in about 33% of pregnant women with PPCM. The connection between the two diseases and the mechanism of PPCM is poorly understood. The Harvard Medical School (HMS) team did not set out to investigate the cause of PPCM but instead stumbled upon it serendipitously while investigating the proangiogenic functions of peroxisome proliferationactivated receptor-g coactivator 1a (PPARGC1A; PGC-1a) in the heart. The researchers were breeding heart-specific Pgc-1a knockout mice and noticed knockout females died after delivering only one or two litters, whereas wild-type females delivered five or more litters without incident. Compared with knockout males, or knockout females that had not yet been pregnant, the postpartum knockout females had enlarged, fibrotic hearts, decreased vascular density in the heart and other signs of cardiomyopathy. Additional experiments in the knockout mice confirmed that lack of Pgc-1a downregulated two proangiogenic pathways in the heart to cause PPCM. These findings led the group to speculate that human PPCM might also result from an angiogenic deficiency. The researchers suspected the culprit was a soluble form of VEGF receptor 1 (FLT1; VEGFR-1). Soluble FLT1 (sFLT1) is an antiangiogenic factor normally secreted by the placenta in late pregnancy, resulting in increased serum levels during the peripartum period. However, the levels are much greater in peripartum women with pre-eclampsia than in healthy peripartum women. 2 In healthy and most pre-eclampsic peripartum women, serum levels of sFLT1 return to normal, prepregnancy levels within three days after delivery. The team found that at 4-6 weeks after delivery, sFLT1 levels were 5-to 10-fold higher in women who had pre-eclampsia and PPCM than in postpartum women who did not have either condition. Next, the team showed that in prepartum women with pre-eclampsia, higher sFLT1 correlated with lower cardiac function as measured by echocardiography. Similar cardiac dysfunction, cardiomyopathy and heart failure occurred when murine sFlt1 was given to pregnant wildtype mice, nonpregnant wild-type mice and nonpregnant cardiacspecific Pgc-1a knockout mice. Data were reported in Nature. 1 Collectively, the findings suggest increased levels of sFLT1 cause PPCM that is associated with pre-eclampsia. The results also suggest that lowering sFLT1 levels could help treat PPCM, team leader Zoltan Arany told SciBX. "We also think-but don't know yet-that the mechanism we describe in this study will apply to all cases of PPCM, not just the onethird associated with pre-eclampsia, " he said.
doi:10.1038/scibx.2012.538 fatcat:c4wtl4a4wrd7fjahg4kgfx4mxe