Ayesha Sayyed

Background: Peripartum cardiomyopathy (PPCM), the most common dilated cardiomyopathy affecting previously heart-healthy women during late-term pregnancy, occurs due to left ventricular (LV) systolic dysfunction.¹ Factors such as increased maternal age, multifetal pregnancies, pre-eclampsia, hypertension, tocolytic usage, and obesity, increase the risk of PPCM.^2-5 PPCM is underdiagnosed due to overlapping symptoms with pregnancy such as peripheral edema, fatigue, tachycardia, tachypnea, palpitations, and dizziness.^2-5 Physical findings such as left ventricular ejection fraction (LVEF) less than 45%, pulmonary congestion, elevated vasoinhibin serum levels, cardiomegaly, and arrhythmias confirm PPCM.^1-5 Treatment includes standard health failure medications alongside a BOARD regimen (Bromocriptine, Oral heart failure drugs, Anticoagulants, Relaxants, and loop Diuretics).¹ Recovery in PPCM is common, but major adverse events include the use of a left ventricular assist device (LVAD), cardiac transplantation, and death.⁶ Current research challenges include drug side effects.

Objective: This narrative review aims to discuss PPCM’s pathophysiology via the STAT3/NF-κB/miR-146a mechanism and Dopamine D2 Receptor (D2R)-targeted pharmacotherapies.

Search Methods: The review’s methods included a PubMed search from 2018-2025 using keywords” “peripartum cardiomyopathy,” “cathepsin D,” “D2R agonist,” “Prolactin,” and “NF-κB/miR-146a pathway”.

Results: Overall, studies found that dysregulation of the signal transducer and activator of transcription 3 (STAT3) pathway is PPCM’s main pathophysiological mechanism.^1-5 The STAT3 pathway generates a defensive effect against hypoxia-induced cardiomyocyte injury.^1-5 In a mouse model, female mice with a cardiomyocyte‐specific STAT3 knockout developed heart failure (HF) after two consecutive pregnancies due to imbalanced oxidative stress.¹ Oxidative stress, caused by the downregulation of MnSOD— a reactive oxygen species (ROS) scavenging enzyme— leads to Cathepsin D activation. ⁴ This protease cleaves 23 kDa prolactin (PRL) into vasoinhibin, a cardiotoxic 16 kDa fragment that compromises cardiomyocyte integrity.⁴  A study found Cathepsin-D levels— associated with greater left atrial diameter and decreased LVEF— were higher in PPCM women than in healthy controls. Vasoinhibin, utilizing nuclear factor kappa‐B (NF‐ κB), upregulates microRNA (miR)‐146a in endothelial cells. miR-146a mediates vascular apoptosis, anti-angiogenesis, fibrosis, and impaired cardiac ErbB4 signalling.⁶ A study found that elevated plasma activation inhibitor-1 (PAI-1), a potential biomarker involved in the NF-κB/miR-146a pathway, promotes fibrosis and inflammation in PPCM.⁷ Bromocriptine, a dopamine agonist, promotes cardiomyocyte recovery by inhibiting prolactin (PRL) production.³ In a rat model with aortocaval fistula-induced cardiac hypertrophy, bromocriptine treatment decreased the hypertrophy index through increased cardiac expression of the PRL receptor and D2 receptor.⁸ In another retrospective study, PPCM-diagnosed females receiving bromocriptine alongside standard HF regimen, experienced fewer adverse maternal outcomes— readmission, severe LV dysfunction, death— than controls receiving only standard HF treatment.⁹ However, bromocriptine acts on various receptors, like D1, D2, adrenergic α, and serotonin receptors leading to unwanted side effects such as orthostatic hypotension and thrombotic events complicating pre-existing cardiac instability in PPCM.¹ Cabergoline, a more selective D2R agonist, has reduced adverse effects, decreased supply disruptions, and a longer half life.¹ In a mouse model, STAT3 knockout mice treated with cabergoline showed comparable reductions to bromocriptine in myocardial fibrosis, collagen deposition, and hypertrophy.¹ Similarly cabergoline treatment yielded decreased biomarkers of PPCM, miR-146a and PAI-1.¹ These findings support selective dopamine D2 agonists, like cabergoline, as a favorable alternate PPCM pharmacotherapy with higher specificity.

Conclusion:  Selective D2 agonists such as cabergoline show promising comparable results to bromocriptine in PPCM treatment by inhibiting prolactin secretion and attenuating STAT3 deficiency. More research is needed on alternatives to prolactin inhibition with breastfeeding PPCM mothers.

Works Cited

1. Pfeffer TJ, Mueller JH, Haebel L, et al. Cabergoline treatment promotes myocardial recovery in peripartum cardiomyopathy. ESC Heart Fail. 2023;10(1):465-477. doi:10.1002/ehf2.14210
2. Davis MB, Arany Z, McNamara DM, Goland S, Elkayam U. Peripartum Cardiomyopathy: JACC State-of-the-Art Review. J Am Coll Cardiol. 2020;75(2):207-221. doi:10.1016/j.jacc.2019.11.014
3. Farrell AS, Kuller JA, Goldstein SA, Dotters-Katz SK. Peripartum Cardiomyopathy. Obstet Gynecol Surv. 2021;76(8):485-492. doi:10.1097/OGX.0000000000000903
4. Iorgoveanu C, Zaghloul A, Ashwath M. Peripartum cardiomyopathy: a review. Heart Fail Rev. 2021;26(6):1287-1296. doi:10.1007/s10741-020-10061-x
5. Rodriguez Ziccardi M, Siddique MS. Peripartum Cardiomyopathy. In: StatPearls. Treasure Island (FL): StatPearls Publishing; July 17, 2023.
6. Polsinelli VB, Hanley-Yanez K, McTiernan CF, et al. Cathepsin-D and outcomes in peripartum cardiomyopathy: Results from IPAC. Am Heart J Plus. 2024;49:100489. Published 2024 Dec 9. doi:10.1016/j.ahjo.2024.100489
7. Ricke-Hoch M, Hoes MF, Pfeffer TJ, et al. In peripartum cardiomyopathy plasminogen activator inhibitor-1 is a potential new biomarker with controversial roles. Cardiovasc Res. 2020;116(11):1875-1886. doi:10.1093/cvr/cvz300
8. Aguayo-Cerón KA, Calzada-Mendoza CC, Méndez-Bolaina E, Romero-Nava R, Ocharan-Hernández ME. The regulatory effect of bromocriptine on cardiac hypertrophy by prolactin and D2 receptor modulation.
9. van der Meer P, van Essen BJ, Viljoen C, et al. Bromocriptine treatment and outcomes in peripartum cardiomyopathy: the EORP PPCM registry. Eur Heart J. 2025;46(11):1017-1027. doi:10.1093/eurheartj/ehae559