Remarks on the Prolactin Hypothesis of Peripartum Cardiomyopathy

A seminal study in 2007 introduced the hypothesis that an antiangiogenic prolactin fragment with a molecular mass of 16 kDa is a key pathological mediator of peripartum cardiomyopathy (PPCM) (1). The study reported that this fragment is enzymatically generated by the cleavage of full-length prolactin with the lysosomal aspartyl protease cathepsin D. Upon excessive generation, possibly due to high pituitary prolactin secretion near term or postpartum and an enhanced oxidative micro-environment, this prolactin fragment would impair myocardial microvascularization and thereby contribute to myocardial dysfunction. Accordingly, a new therapy for PPCM was explored using the dopamine D2 receptor agonists, cabergoline and bromocriptine. Treatment with bromocriptine is currently being evaluated in a multicenter clinical trial (NCT00998556) (2). The concept underlying this putative therapy is the inhibition of the generation of the prolactin fragment by substrate depletion , i.e., the inhibition of pituitary prolactin secretion by activation of dopamine D2 receptors in lactotropes. PPCM is a rare disease which occurred with a frequency of 1 case/3189 live births and an estimated mortality of 1.36–2.05% (confidence interval 0.29–10.8%) from 1990 to 2002 in the United States (3). However, the incidence of PPCM seems to be variable, depending on the geographical region, ethnic background, and other criteria (4, 5). Since the initial discovery, several research, case report, and review articles have been published (5–10) describing signaling mechanisms mediating the deleterious action of the 16-kDa prolactin fragment and supporting the beneficial effects of treatment with dopamine D2 agonists in patients with PPCM. However, there are relevant aspects to the proposed pathological mechanism in PPCM that are absent in these studies with the consequence of limiting the field by pointing to wrong, or incomplete conclusions. In contrast to what is suggested in most of the PPCM-related literature, the 16-kDa prolactin fragment is only one of the several antiangiogenic prolactin fragments derived from prolactin via cathepsin D and other proteolytic enzymes. Altogether, these fragments of different molecular masses comprise a family of proteins termed vasoinhibins (11, 12). Cathepsin D alone can generate four more vasoinhibins by cleaving full-length prolactin at sites other than the one generating the 16-kDa fragment (13). Three of these cathepsin D-generated vasoinhibin isoforms have documented antiangiogenic activity (11, 13)—a notion that should not go unnoticed when studying the 16-kDa vasoinhibin isoform as a key pathologic mediator of PPCM. The possible contribution of other vasoinhibin isoforms to the pathophysiology of PPCM has neither been investigated …