Cabergoline treatment promotes myocardial recovery in peripartum cardiomyopathy

Abstract

Aims Peripartum cardiomyopathy (PPCM) is a rare heart disease, occurring in previously heart‐healthy women during the last month of pregnancy or the first months after delivery due to left ventricular (LV) systolic dysfunction. A common pathomechanistic pathway of PPCM includes increased oxidative stress and the subsequent generation of a cleaved prolactin fragment (16 kDa PRL), which promotes the onset of heart failure (HF) in a microRNA (miR)‐146a‐dependent manner. Inhibition of prolactin secretion with the dopamine D2 receptor (D2R) agonist bromocriptine combined with standard HF therapy supports cardiac recovery. This study examined whether treatment with the more selective D2R agonist cabergoline prevents HF development in an experimental PPCM mouse model and might be used as an alternative treatment regime for PPCM. Methods and results Postpartum (PP) female PPCM‐prone mice with a cardiomyocyte restricted STAT3‐deficiency (αMHC‐Cre tg/+ ; Stat3 fl/fl ; CKO) were treated over two consecutive nursing periods with cabergoline (CKO Cab, 0.5 mg/kg/day) and were compared with bromocriptine treated CKO (CKO Br) and postpartum‐matched WT and CKO mice. Cabergoline treatment in CKO PP mice preserved cardiac function [fractional shortening (FS): CKO Cab: 34.5 ± 9.4% vs. CKO: 22.1 ± 9%, P < 0.05] and prevented the development of cardiac hypertrophy, fibrosis, and inflammation as effective as bromocriptine therapy (FS: CKO Br: 33.4 ± 5.6%). The myocardial up‐regulation of the PPCM biomarkers plasminogen inhibitor activator 1 (PAI‐1) and miR‐146a were prevented by both cabergoline and bromocriptine therapy. A small cohort of three PPCM patients from the German PPCM Registry was treated with cabergoline (1 mg per week for 2 weeks, followed by 0.5 mg per week for another 6 weeks) due to a temporary unavailability of bromocriptine. All PPCM patients initially presented with a severely reduced LV ejection fraction (LVEF: 26 ± 2%). However, at 6 months of follow‐up, LV function (LVEF: 56 ± 2%) fully recovered in all three PPCM patients, and no adverse events were detected. Conclusions In the experimental PPCM mouse model, the selective D2R agonist cabergoline prevents the onset of postpartum HF similar to bromocriptine. In PPCM patients, cabergoline treatment was safe and effective as all patients fully recovered. Cabergoline might serve as a promising alternative to bromocriptine. However, these findings are based on experimental data and a small case series and thus have to be interpreted with caution and should be validated in a larger clinical trial.

Immunometric and functional measurement of endogenous vasoinhibin in human sera

“…The local generation of vasoinhibin is impacted by the levels of PRL produced and secreted by the pituitary gland into the circulation. Such impact is the basis of clinical trials for the treatment of peripartum cardiomyopathy and diabetic retinopathy, where pharmacological interventions at the pituitary level with a dopamine D2 agonist (bromocriptine) or antagonist (levosulpiride) leading to hypoprolactinemia or hyperprolactinemia, respectively, are evaluated for the inhibition and the stimulation of vasoinhibin generation ( 41 – 43 ).…”

An Interesting Case of Peripartum Cardiomyopathy With Biventricular Thrombi

“…Past studies have suggested that prolactin may be involved in the development of PPCM, and have prompted research on prolactin inhibition with bromocriptine in PPCM. The following has also been studied in recent preclinical models where cabergoline has been shown to decrease the onset of PPCM in mice models [ 18 ]. A small prospective study randomized females with PPCM to standard therapy versus standard therapy with bromocriptine and showed modest improvement in clinical outcomes for patients treated with bromocriptine addition, including improved six-month left ventricular function [ 19 ].…”

Editors' highlight picks from 2023 in ESC heart failure

“…Accordingly, interactions between metabolic, microvascular, inflammatory, and haemodynamic parameters are analysed to reveal fine details of myocardial dysfunction in HF phenotypes with distinct aetiologies ranging from Takotsubo cardiomyopathy 49 through severe functional mitral regurgitation, 50 HF complicated by pulmonary hypertension, 51 and HF patients with coronary artery disease (CAD) 52,53 to peripartum cardiomyopathy. 54 Recognition of genetic variants co-segregating with congenital heart disease (CHD) is instrumental for early prenatal diagnosis. Yi et al conducted a translational investigation on a cohort of 398 foetuses with CHD using high level genetic analyses: copy number variant-sequencing (CNV-seq) and exome sequencing (ES).…”

“…Preclinical and translational investigations frequently aim at the molecular drivers of HF pathogenesis. Accordingly, interactions between metabolic, microvascular, inflammatory, and haemodynamic parameters are analysed to reveal fine details of myocardial dysfunction in HF phenotypes with distinct aetiologies ranging from Takotsubo cardiomyopathy 49 through severe functional mitral regurgitation, 50 HF complicated by pulmonary hypertension, 51 and HF patients with coronary artery disease (CAD) 52,53 to peripartum cardiomyopathy 54 …”