Cardiogenic shock complicating peripartum cardiomyopathy benefits from combination therapy with levosimendan and bromocriptine

AIMS: Peripartum cardiomyopathy (PPCM) is characterized by left-ventricular systolic dysfunction. Plasminogen-activator-inhibitor 1 (PAI-1) and 16K-prolactin (PRL) are known drivers of PPCM. Treatment of cardiogenic shock (CS) complicating PPCM is challenging. The calcium sensitizer levosimendan (LS) is considered as a beneficial therapy in CS. There are only sparse data regarding the safety and efficacy of LS-treatment in PPCM. We aimed to investigate the molecular effects and safety of LS-treatment in the PPCM mouse model (cardiomyocyte-specific-knockout of signal-transducer-and-activator-of-transcription 3 (STAT3), CKO) and in patients from the German PPCM registry. METHODS AND RESULTS: In the PPCM mouse model, LS-treatment aggravated postpartum heart failure associated with fibrosis, reduced capillary density, and enhanced mortality, whereas LS-treatment together with the PRL-inhibitor bromocriptine (BR) preserved cardiac function. In CKO hearts, LS induced PAI-1 expression via the upregulation of thrombospondin-1/-4, transforming-growth-factor-β, and activation of SMAD2 that could be prevented by combination with BR. In the German PPCM registry, 17 PPCM patients with CS were treated with LS and BR. Despite the severity of CS, all these patients survived the acute phase, and most patients showed cardiac recovery in the ensuing course of the disease (left ventricular ejection fraction at 3-month follow-up: 40 ± 19%). CONCLUSION: Thus, the combination therapy with LS and BR seems to be a safe and potentially beneficial therapeutic concept for the treatment of PPCM patients with CS. As experimental PPCM mouse data suggest that treatment of PPCM patients in CS with LS alone may worsen cardiac function by enhancing the PRL/PAI-1-dependent pathomechanism, treatment of LS in PPCM patients should always be accompanied by BR treatment.