Background: Peripartum cardiomyopathy (PPCM) is defined as heart failure (HF) secondary to left ventricular (LV) systolic dysfunction towards the end of pregnancy or in the first months after delivery in previously heart-healthy women. A common pathomechanistic pathway of PPCM includes increased oxidative stress and generation of a cleaved prolactin fragment (16 kDa-PRL), which promotes HF through vascular damage. Inhibition of prolactin secretion with the dopamine D2 receptor agonist bromocriptine (Br) in combination with standard HF therapy supports cardiac recovery. As Br availability is limited, often alternative dopamine D2 agonists are used. This study examined whether the treatment with the dopamine D2 agonist cabergoline (Cab) prevents HF in the experimental PPCM mouse model and in PPCM patients.

Methods and results:

Postpartum (PP) female PPCM-prone mice with a cardiomyocyte restricted STAT3-deficiency (alphaMHC-Cretg/+;Stat3fl/fl; CKO) were treated with Cab or Br over two pregnancies and nursing periods. Thereafter, female CKO mice with PPCM (CKO-PP) showed impaired cardiac function compared to wildtype (STAT3flox/flox: WT) mice (%FS: CKO-PP: 22.1±9.0 vs. WT-PP: 37.2±5.4, P<0.01, n=8-9). Treatment starting two days before delivery until 3 weeks postpartum over two consecutive pregnancies and nursing periods with Br (%FS: 33.4±5.6, P<0.05 vs CKO-PP, n=8) or Cab (%FS: 34.5±9.4, P<0.05 vs CKO-PP, n=8) preserved cardiac function and prevented fibrosis and inflammation in CKO-PP mice equally well. Postpartum HF development in CKO female mice was associated with enhanced cardiac hypertrophy (increased ANP and ANKRD1 mRNA expression, cardiomyocyte cross-sectional area and heart weight/body weight or heart weight/ tibia length ratio). Moreover, increased collagen deposits and elevated inflammation (increased CD68 positive infiltrates and mRNA expression of the macrophage marker EGF-like module-containing mucin-like hormone receptor-like 1, also known as F4/80 or Adgre1) were observed in CKO PP hearts. Both Cab and Br prevented the development of hypertrophy, fibrosis and inflammation. In line with these findings, the cardiac upregulation of the PPCM biomarkers PAI-1 and miR-146a (WT-PP: 100±10%, CKO-PP: 137±19%*, CKO-PP Br: 94±24%, CKO-PP Cab: 105±25%, *P<0.05 vs WT-PP) were prevented by Cab and Br treatment.

Three PPCM patients were treated with Cab at Hannover Medical School. All patients presented with a severely reduced LV function (LVEF 25-30%). At follow up (2-7 months) LV function improved in all three patients to an LVEF between 50% and 58%. No Cab related complications or adverse effects were detected.

Conclusion:

Cab treatment prevents HF onset in the experimental CKO PPCM mouse model and in a small number of PPCM patients equally well as Br, and might therefore be an alternative efficient treatment regime in PPCM, whenever Br is not available. However, these results need to be confirmed in larger clinical studies.