Cardiac Physiology

An Unkind Cut Leading to a Broken Heart

Science's STKE  13 Feb 2007:
Vol. 2007, Issue 373, pp. tw53
DOI: 10.1126/stke.3732007tw53

Postpartum (or peripartum) cardiomyopathy (PPCM), which occurs late in pregnancy--or up to a few months after delivery--is associated with acute onset of heart failure in women with no history of heart disease (see Leinwand). Hilfiker-Kleiner et al. found that female mice lacking cardiomyocyte STAT3 (signal transducer and activator of transcription 3) developed PPCM. Pregnancy is associated with cardiac hypertrophy and increased capillary density, physiological changes that occurred in mice lacking cardiac STAT3. However, unlike mice that expressed cardiac STAT3, postpartum mice lacking cardiac STAT3 (CKO-PP mice) lost the increased capillary density. CKO-PP mice also had an attenuated increase in cardiac manganese superoxide dismutase and excessive cardiac production of reactive oxygen species, leading to increased abundance and activity of the proteolytic enzyme cathepsin D. Further, cardiac tissue from CK-PP mice stimulated cleavage of prolactin (a cathepsin D substrate) into an antiangiogenic 16-kD form. Increasing circulating prolactin stimulated cardiac damage in mice overexpressing cardiac cathepsin D, and persistent cardiac expression of 16-kD prolactin led to a pregnancy-independent decrease in capillary density and cardiac function. In contrast, pharmacological inhibition of prolactin secretion prevented PPCM. Analysis of left-ventricular tissue from women with PPCM revealed decreased STAT3 abundance; moreover, cathepsin D activity and 16-kD prolactin were increased in their serum. A preliminary study suggested that inhibiting prolactin release was protective of cardiac function in women at high risk of PPCM. Thus, the authors suggest that cardiac STAT3 is critical to postpartum cardiac function and propose that inhibiting prolactin release may represent a viable approach to PPCM treatment.

D. Hilfiker-Kleiner, K. Kaminski, E. Podewski, T. Bonda, A. Schaefer, K. Sliwa, O. Forster, A. Quint, U. Landmesser, C. Doerries, M. Luchtefeld, V. Poli, M. D. Schneider, J.-L. Balligand, F. Desjardins, A. Ansari, I. Struman, N. Q. N. Nguyen, N. H. Zschemisch, G. Klein, G. Heusch, R. Schulz, A. Hilfiker, H. Drexler, A cathepsin D-cleaved 16 kDa form of prolactin mediates postpartum cardiomyopathy. Cell 128, 589-600 (2007). [Online Journal]

L. A. Leinwand, Molecular events underlying pregnancy-induced cardiomyopathy. Cell 128, 437-438 (2007). [Online Journal]