Peripartum cardiomyopathy (PPCM) is a heart disease affecting women during the peripartum period. Treatment of cardiogenic shock (CS) complicating PPCM is challenging. The calcium (Ca) sensitizer levosimendan (LS) is considered as a beneficial therapy in CS. So far there are only sparse data regarding the safety and efficacy of treatment with LS in PPCM.

Methods and Results

Mice with a cardiomyocyte-specific deletion of STAT3 (CKO) develop PPCM with left ventricular (LV) dysfunction after two pregnancies and nursing periods (Tbl). Treatment with LS was associated with enhanced LV dilatation and further reduced contractility in CKO-PP (Tbl), whereas treatment with BR preserved cardiac structure and function. Cotreatment of LS and BR (LS+BR) completely prevented heart failure (Tbl) in CKO-PP. LS treatment alone was not able to attenuate myocardial hypertrophy (Tbl, increased ANP mRNA levels), fibrosis (increased Collagen 1a1 mRNA levels) and inflammation (increased CD45 and CD68 positive infiltrates and Adgre1 mRNA levels) in CKO-PP. Both, untreated and LS treated CKO-PP showed reduced cardiac vascularization compared to WT-PP. In addition, analysis of adenylate cyclases (Adcy) 5 and 6 expression revealed increased mRNA expression of Adcy5 relative to Adcy6 in untreated and LS treated CKO-PP compared to WT-PP. Ca sensitivity was reduced in isolated cardiomyocytes from LV tissue from CKO-PP compared to WT-PP. LS treatment increased Ca sensitivity in CKO-PP.

BR alone or LS+BR reduced hypertrophy (Tbl), fibrosis and inflammation and was associated with normalized mRNA levels of ANP, Collagen 1a1, and Adgre1. Furthermore, Adcy5 to Adcy6 ratio normalized to WT-PP levels in CKO-PP treated with BR and LS+BR. Moreover, LS+BR treatment in CKO-PP was associated with improved cardiac vascularization (increased VE-Cadherin mRNA expression) compared to CKO-PP untreated and LS treated mice. Treatment with BR alone and LS+BR completely restored Ca sensitivity in isolated cardiomyocytes from CKO-PP to WT-PP level. In addition, maximum force in isolated cardiomyocytes was significantly reduced in CKO-PP treated with LS compared to CKO-PP treated with NaCl, BR, and BR+LS.

In the German PPCM registry 14 PPCM patients with CS had received LS in combination with BR. LVEF was severely reduced (18±8%) at baseline and mechanical circulatory support (Impella, ECMO or IABP) was needed in 71%. All patients survived the acute phase of CS (30-days survival: 100%).

Conclusion:

Treatment of PPCM mice with LS appears to aggravate heart failure, whereas the combination of BR and LS seem to be beneficial. Regulation of Adcy isoforms, cAMP signaling and Ca handling as well as fibrosis and inflammation might be involved in the LS induced pathogenesis of PPCM and seem to be counteracted by BR treatment. Moreover, in CS the combination of LS and BR seems more protective than BR alone, a feature supported by clinical data, showing a 100% survival rate of the CS episode in PPCM patients treated with BR+LS.

*P<0.05 vs WT NaCl, ^#P<0.05 vs CKO NaCl, ^§P<0.05 vs CKO LS