Combination of levosimendan with bromocriptine is safe and effective in cardiogenic shock complicating peripartum cardiomyopathy

Peripartum cardiomyopathy (PPCM) is a heart disease characterized by left-ventricular systolic dysfunction, with peripartum onset in heart healthy women. Plasminogen-activator-inhibitor 1 (PAI-1) is a known driver of PPCM, mediating fibrosis and anti-angiogenic effects. 

Compared to other cardiomyopathies, PPCM patients have a high chance of full cardiac recovery. However, treatment of cardiogenic shock (CS) complicating PPCM is still challenging. The calcium sensitizer levosimendan (LS) is considered as a beneficial therapy in CS, but so far, there are only sparse data regarding the safety and efficacy of LS treatment in PPCM. 

In the PPCM mouse model (cardiomyocyte-specific knockout of STAT3, CKO) LS treatment alone aggravated postpartum (PP) heart failure (HF) associated with enhanced mortality, whereas treatment with LS in combination with bromocriptine (BR) preserved cardiac function (%FS: WT PP 38±6, CKO PP 23±6, CKO PP LS 15±6, CKO BR 32±8, CKO PP LS+BR 36±7, P<0.05) and prevented mortality. Isolated cardiomyocytes (CMs) from CKO PP mice showed substantially reduced calcium sensitivity of force generation compared to WT PP mice, while calcium-sensitivity of CMs from CKO PP mice treated with BR or LS+BR was normal. Indeed, LS treatment of CKO PP mice could partially restore normal calcium sensitivity of the CMs.

To investigate the specific effects of LS treatment to the cardiac signaling system in CKO mice, CKO and WT mice received a single LS injection and the alterations on cardiac mRNA and protein expression after 24h were analyzed. By using a mouse angiogenesis proteome profiler array, we identified an increase of PAI-1 mRNA and protein expression in LS-treated CKO compared to NaCl-treated CKO and to LS-treated WT hearts. Moreover, LS treatment induced a specific upregulation of thrombospondin (THBS) 1 and 4, transforming growth factor beta (TGF beta and activation of SMAD2 in CKO LVs. In contrast, LS showed no effect on the expression and activation in WT LVs. As a proof-of-concept, we demonstrated that a single dose of THBS-1 and -4 is inducing cardiac PAI-1 expression in WT mice. Indeed, CKO PP LS LVs revealed significant increased protein expression of THBS-1 and -4 and PAI-1 that could be prevented by the combination therapy with BR. 

In the German PPCM registry, 17 PPCM patients with CS complicating PPCM that received LS in combination with BR, could be identified. At diagnosis, cardiac function was severely reduced  (LVEF 17±8%) and CS was pronounced. Mechanical circulatory support (Impella, ECMO or IABP) was needed in 81% of the patients and most patients (75%) required intubation and mandatory ventilation.  

Despite the severity of CS, all patients treated with LS in combination with BR survived the acute phase and most patients showed cardiac recovery in the further course of the disease (6-months survival: 100%; LVEF at 6-months follow-up: 51±10%). 

PPCM CKO mice revealed that LS treatment aggravated LV dysfunction whereas combination therapy with LS+BR prevented the onset of HF. These effects seem to be mediated by an increased induction of the PAI-1 pathomechanism via upregulation of THBS-1 and -4 potentially promoting fibrosis and endothelial damage in STAT3-deficient hearts. Thus, combination therapy with LS+BR seems to be a safe and beneficial therapeutic concept for the treatment of CS complicating PPCM in patients.