Emily Bininger

Background: Peripartum cardiomyopathy (PCM), the most common dilated cardiomyopathy in late-term pregnant women persisting up to 5 months postpartum, involves non-ischemic systolic heart failure due to decreased left ventricular function¹.  PCM’s multifactorial nature includes genetic, environmental, hormonal, and pregnancy-related changes.^1-4. PCM diagnosis can overlap with normal pregnancy symptoms such as fatigue, orthopnea, edema, and chest pain¹, but can be diagnosed through physical exams and tests showing decreased left ventricular ejection fraction (LVEF) less than 45%, pulmonary congestion, cardiomegaly, arrhythmias, and elevated 16-kDa prolactin serum levels ^1,4,5. The treatment includes standard health failure medications alongside the comprehensive BOARD regimen (Bromocriptine the Dopamine D2 agonist, Oral heart failure drugs, Anticoagulants, Relaxants, and loop Diuretics)^6,10. PCM poses significant health risks because there is no known prevention for these previously healthy women experiencing severe complications such as left ventricular systolic dysfunction, cardiomyocyte and vascular epithelial cell apoptosis, and even death⁶. Research barriers include drug side effects and the condition’s rarity.

Objectives: This narrative review aims to discuss PCM’s pathophysiology via the Notch/Stat3 mechanism and current pharmacotherapeutic studies targeting this mechanism via the Dopamine D2 Receptor (D2R).

Search Methods: The review’s methods included a PubMed search from 2018-2024 using key words” “peripartum cardiomyopathy” “dilated cardiomyopathy” “pharmacotherapy” “D2 Receptor” “Prolactin”.

Results: The studies found that dysregulation of Notch and signal transducer and activator of transcription 3 (Stat3) pathways is PCM’s main pathophysiological mechanism, safeguarding angiogenesis and cardiomyocyte integrity^6,7. The Notch pathway regulates vascular endothelial growth factor (VEGF crucial for vascular growth, hematopoiesis, and cardiomyocyte survival^6,7. In a mouse model, peripartum mice given Notch inhibitor, LY-411575, had increased myocardial interstitial fibrosis, hypertrophy, and injury upon histological analysis⁷. Additionally, Notch product Hes1 influences Stat3 activity, connecting the two pathways⁷. Downregulating Notch/Hes1/Stat3, often due to oxidative stress in pregnancy, triggers cathepsin D fragmentation of the pregnancy hormone prolactin into a cardiotoxic 16-kDa fragment, causing subsequent microRNA-146a-induced endothelial dysfunction, vascular apoptosis, fibrosis, and cardiomyocyte death^6,7. A study found that peripartum conditional knockout mice with STAT3 deficiency receiving D2R agonist bromocriptine or cabergoline treatment developed less myocardial fibrosis, collagen deposits, and hypertrophy compared to controls upon staining analysis⁶. Considering benefit in many systemic diseases, animal models with induced heart failure and treated with D2 agonists inhibited prolactin secretion and decreased myocardial injury risk^6,8,9. In a small study, patients treated with BOARD had reduced prolactin levels, improved LVEF, and full cardiovascular recovery following PCM diagnosis⁶. In one of the largest clinical studies to date, BOARD treatment of PCM improved LVEF above 50% and decreased mortality after 5 years¹⁰. These findings support dopamine D2 agonists and anticoagulants as an integral part of PCM pharmacotherapy^6,10. However, long-term use may contribute to hypertension and arrhythmias, requiring careful management^9,10.

Conclusion: D2 agonists bromocriptine and cabergoline show promising results in PCM treatment by inhibiting prolactin secretion and mitigating STAT3 deficiency. Appropriate long-term management remains essential to treatment. More research is needed on best practices for physicians discussing prolactin inhibition with breastfeeding mothers with PCM mothers.

Work Cited:

1. 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
2. Sliwa K, Bauersachs J, Arany Z, Spracklen TF, Hilfiker-Kleiner D. Peripartum cardiomyopathy: from genetics to management. European Heart Journal. 2021;42(32):3094-3102. doi:10.1093/eurheartj/ehab458
3. Schaufelberger M. Cardiomyopathy and pregnancy. Heart. 2019;105(20):1543-1551. doi:10.1136/heartjnl-2018-313476
4. Kryczka KE, Demkow M, Dzielińska Z. Biomarkers in Peripartum Cardiomyopathy-What We Know and What Is Still to Be Found. Biomolecules. 2024;14(1):103. doi:10.3390/biom14010103
5. Sliwa K, Petrie MC, van der Meer P, et al. Clinical presentation, management, and 6-month outcomes in women with peripartum cardiomyopathy: an ESC EORP registry. European Heart Journal. 2020;41(39):3787-3797. doi:10.1093/eurheartj/ehaa455
6. Pfeffer TJ, Mueller JH, Haebel L, et al. Cabergoline treatment promotes myocardial recovery in peripartum cardiomyopathy. ESC Heart Failure. 2023;10(1):465-477. doi:10.1002/ehf2.14210
7. Zhu RR, Chen Q, Liu ZB, Ruan HG, Wu QC, Zhou XL. Inhibition of the Notch1 pathway induces peripartum cardiomyopathy. J Cell Mol Med. 2020;24(14):7907-7914. doi:10.1111/jcmm.15423
8. Fouad Shalaby M, Latif HAAE, Yamani ME, Galal MA, Kamal S, Sindi I. Protective Role of Sarpogrelate in Combination with Bromocriptine and Cabergoline for Treatment of Diabetes in Alloxan-induced Diabetic Rats. Curr Ther Res Clin Exp. 2021;95:100647. doi:10.1016/j.curtheres.2021.100647
9. 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. Clin Exp Hypertens. 2020;42(7):675-679. doi:10.1080/10641963.2020.1772814
10. Moulig V, Pfeffer TJ, Ricke-Hoch M, et al. Long-term follow-up in peripartum cardiomyopathy patients with contemporary treatment: low mortality, high cardiac recovery, but significant cardiovascular co-morbidities. Eur J Heart Fail. 2019;21(12):1534-1542. doi:10.1002/ejhf.1624