A B M Nasibul Alam^*, Natalia P. Ballestas, Tatjana Blazin, Dhruvil Prajapati, Linha (Lina) M. Mohammed, Meera Dhavale, Mohamed K. Abdelaal, Jihan A. Mostafa

California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

*Corresponding Author: A B M Nasibul Alam, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA

Abstract
In the late antepartum and the early postpartum period, peripartum cardiomyopathy (PPCM) is an important etiology of heart failure. A disease of increasing severity, PPCM has substantial heterogeneity in its regional and ethnic distribution. Besides, findings of multiple studies conducted in the last two decades have demonstrated that a subset of PPCM might comprise a portion of the Familial Dilated Cardiomyopathy (DCM) syndrome.

A research article published in 2008 demonstrated that 16 kDa prolactin is involved in the pathogenesis of PPCM. Consequently, multiple studies were conducted to assess the efficacy of bromocriptine, a prolactin release inhibitor drug as a disease-specific therapeutic agent for PPCM. Analysis of these studies in our article showed that bromocriptine improves clinical and echocardiographic outcomes in PPCM patients. However, it is important to mention that there are some valid concerns regarding the acceptance of bromocriptine as a therapeutic option in PPCM due to certain deficiencies of the available data including a small number of studies, and the studies themselves having various limitations, the lack of diversity in the study population is a crucial one. In addition, there are concerns regarding the prothrombotic adverse effects of bromocriptine in PPCM patients. Hence, it has been recommended to use additional prophylactic anticoagulation along with bromocriptine. The available data suggest that prophylactic anticoagulation might be effective in reducing or even eliminating the risk of thrombosis associated with the use of bromocriptine in PPCM.

Therefore, we recommend conducting more studies, especially large-scale international studies, with diverse study populations before reaching any conclusion regarding the efficacy and safety of bromocriptine in PPCM. The already available pieces of information that we have summarized and reviewed in our article would assist in planning and designing such studies.

Introduction
In 1971, Demakis et al. [1] first defined peripartum cardiomyopathy (PPCM) based on 3 specific criteria. One of these criteria limited the diagnosis of PPCM to the period extending from the last gestational month to the first five months in the postpartum period. Since then, the definition of PPCM has evolved, and been expanded.

A recent definition of PPCM given by a working group on PPCM of European Society of Cardiology [2] defines PPCM as “ idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found. It is a disease of exclusion. The left ventricle may not be dilated but the ejection fraction is nearly always reduced below 45 %.”

The incidence of PPCM is on the rise [3, 4], and it greatly varies from country to country (figure 1) [3,5-8]. For example, in Nigeria, the incidence of PPCM was found to be 1 in 102 deliveries [5] whereas, in Denmark, the incidence was estimated as 1 in 10,149 deliveries [8]. A major factor contributing to this wide variation in incidence rates may be attributed to the fact that African ancestry is considered to be an important risk factor for PPCM [3,9]. Moreover, the prognosis is worse in women of African origin in comparison to other ethnic groups [10]. In addition, genetic susceptibility may contribute to a higher incidence of PPCM in certain regions compared to the rest of the world [11]. Again, it has also been suggested that genetic predisposition may be a poor prognostic factor for PPCM [12,28,45].

Figure 1: Incidence of PPCM (per 100000 births) in different countries around the world

Discussion
PPCM Pathophysiology
Multiple factors are implied to be responsible for the pathogenesis of PPCM. In the last two decades, various theories have been put forward to comprehensively explain the complex interplay among different etiological factors responsible for PPCM. The two-hit model of PPCM pathogenesis is one of these theories.

According to this model, it is hypothesized that the late gestational antiangiogenic hormonal environment (1^st hit) causes PPCM in an already susceptible woman (2^nd hit) [19]. (Figure 2)

Figure 2: The two-hit hypothesis of Peripartum Cardiomyopathy. sFlt-1 = soluble Fms-like tyrosine 1

Explanation of the First Hit
Hilfiker-Kleiner et al [12] demonstrated that excess secretion of Cathepsin D (CD) from cardiac myocyte in STAT knockout (KO) mice lead to cleavage of prolactin into a 16kD fragment. Endothelium exposed to this 16kD fragment induces expression of microRNA146a, which in turn is taken up by the adjacent cardiomyocytes, and subsequently, anti-apoptotic genes are suppressed in these cardiomyocytes [28]. As a result, increased apoptosis occurs in cardiomyocytes leading to PPCM [13, 19]. This pathophysiology is illustrated in Figure 3.

Figure 3: Pathophysiology of Prolactin mediated cardiomyocyte apoptosis/dysfunction.

In another study [20], it was demonstrated that PGC-1 alpha, a transcription coactivator of energy metabolism in various cell types, leads to Angio toxicity in the late gestational period. According to this study, two pathways are implied to be involved in the development of such Angio toxicity. One is the activation of the aforementioned antiangiogenic 16 kD prolactin mediated pathway, and the other one is the loss of the proangiogenic Vascular Endothelial Growth Factor (VEGF) mediated pathway. The effects of loss of VEGF are accentuated by increased placental secretion of soluble Fms-like tyrosine 1 (sFlt-1) in late gestation. Under normal circumstances, VEGF protects against the cardiotoxic effects of sFlt-1. But the absence of PGC-1 alpha significantly reduces the production of VEGF resulting in the impediment of its cardioprotective activity. Interestingly, it was noticed in this study that the recovery of PGC-1 alpha cardiac KO mice was achieved with the combination of bromocriptine and VEGF, not bromocriptine alone.

Bello et al. [19] suggested that genetic predisposition and environmental factors such as viral myocarditis possibly comprise the 2^nd hit. It has also been speculated that hypertension, nutritional factors (i.e., selenium deficiency, or autoimmunity can play a role in further increasing the susceptibility. Therefore, a ‘multifactorial susceptibility’ theory of PPCM has been implied, but more evidence is required to support it [21]. 

Role of Bromocriptine in the Management of PPCM
Benefit of Bromocriptine as a therapeutic agent in PPCM Bromocriptine is a semisynthetic ergot derivative. It is a D2 receptor (D2R) agonist and D1 receptor (D1) antagonist. It exerts its prolactin inhibitory function by binding with and activating D2R via several complex and intricate pathways. Figure 4 gives a glimpse into the array of effects D2R activation has on prolactin secretion and synthesis [24, 25, 40].

Figure 4: Impacts of Type 2 Dopamine Receptor (D2R) activation on prolactin

The findings of the study by Sliwa K et al. [27] were supported by a cohort study conducted by Haghikia et al. [28] which had a study population of 115 and a baseline LVEF of 27 ± 9 %. The majority (n=64) of them received a combination of conventional therapy for heart failure and bromocriptine. Among those who were available for the follow-up (n=96), an overwhelming majority (92 %) of the patients in the bromocriptine group showed partial or complete recovery while only 72 % of the patients in the non-bromocriptine group showed recovery. The characteristics and findings of this study are summarized in Table 1. One of the limitations of this study is that the data analyzed did not have proper quality control. Another limitation is that 16.5% of the study population was lost to follow-up. In addition, it was not a randomized placebo-controlled clinical trial [28].

Echoing the findings of the studies conducted by Sliwa K et al. [27] and Haghikia et al. [28], a Randomized Clinical Trial (RCT) of 96 women of African ancestry in Burkina Faso demonstrated better clinical and echocardiographic outcomes in PPCM patients receiving bromocriptine therapy. The baseline mean LVEF was 37.2 ± 6.6 % in patients (n=48) treated with conventional heart failure therapy and bromocriptine, and 37.5 ± 4.8 % in patients (n=48) treated with conventional heart failure therapy alone. Within just two weeks, the group receiving bromocriptine showed better improvement in LVEF compared to the group that did not receive it (LVEF = 41.1 ± 2.1 % vs. 39.6 ± 5.9 %, p=0.021). At six months follow-up, cumulative death was found to be lower (16.6%) in the group treated by bromocriptine compared to the group that was not treated by bromocriptine (29.1 %) (p=0.0001). At 2 months follow-up, the group receiving bromocriptine showed significant improvement in the echocardiographic findings. In this follow-up, it was observed that LVEF was 53.9 ± 4.1 % in the group receiving bromocriptine and 45.9 ± 5.9 % in the group not receiving bromocriptine (p= 0.001) [29]. (Table 1)

In addition, interesting findings were noticed in a study conducted in Germany. In this multicenter prospective randomized study, two different bromocriptine regimens were compared in 63 PPCM patients who were randomized into two groups. One group containing 32 patients received a short course of bromocriptine (2.5 mg bromocriptine for  one week)  and the  other  group containing  31 patients received a longer course of bromocriptine (five mg  bromocriptine for two weeks followed by 2.5 mg for six weeks). Both groups received standard heart failure therapy and anticoagulant. At six months follow up, the LVEF improved in both the groups (from 28 ± 10 % to 49 ± 12 % in the short-course group and from 27 ± 10 % to 51 ± 10 % in the long-course group). However, the difference in delta-LVEF between the short-course (+ 21 ± 11 %) and the long- course group (+ 24 ± 11 %) was not statistically significant (P = 0.381). Besides, more patients in the long-course group (68 %) showed full recovery (LVEF ≥ 50 %) compared to the short-course group (52 %); however, it was also not statistically significant (p=0.283) [30]. (Table 1)

It is important to mention that although there was no placebo control group in this study, a comparison of a subgroup of this the study characterized by a baseline LVEF of less than 30 % with a subgroup of the Investigation in Pregnancy Associated-Cardiomyopathy (IPAC) study with the same cut off value for LVEF demonstrated a greater clinical recovery in the subgroup of this study. It should be noted that the IPAC subgroup did not receive additional bromocriptine treatment [31]. This favors the narrative that bromocriptine provides a better clinical outcome in PPCM]. However, this finding should be interpreted with caution as the IPAC study subgroup had a much higher percentage of patients of African origin (27 % vs. 2 %) for whom the prognosis tends to be worse.

In a retrospective cohort study by Maxime Tremblay-Gravel et al. [31], bromocriptine was found to be independently associated with better recovery of the left ventricular function. However, in this study, the analysis failed to show any significant association of bromocriptine with mortality in PPCM patients. The characteristics and findings of this study are summarized in Table 1. It should be noted that a very small number of patients (eight) that received bromocriptine treatment were included in this study. Moreover, it was a non-randomized retrospective observational study making it susceptible to several confounders and biases including lack of monitoring of dose and compliance of bromocriptine outside of the hospital, and lack of adjustment of the ethnic background in multivariable analyses.

All of the aforementioned studies have elucidated that bromocriptine has a positive impact on LV function recovery. Recently another study showed that bromocriptine treatment along with standard heart failure therapy is associated with a high rate of recovery of right ventricular function. It is worth mentioning that there was no placebo control arm in this study [32].

On the contrary to these findings which provide supportive evidence in favor of bromocriptine use in PPCM, Anne Schjødt Ersbøll et al.

[38] argued that more evidence is required before considering bromocriptine for PPCM treatment based on post hoc analyses of outcome in two subgroups with baseline LVEF < 30 % in a Danish cohort of PPCM patients. One subgroup had 13 women treated with a prolactin inhibitor drug cabergoline for two days and another subgroup comprised of 23 women without any prolactin inhibitor drug. They found no statistically significant difference in the full recovery rate between these two subgroups. However, this study has significant limitations. Cabergoline was used for only two days instead of the one-week regimen used in most of the studies that showed a better outcome in PPCM with bromocriptine use. Moreover, it was a small, retrospective study.

There have been multiple case reports of procoagulant adverse effects (i.e. MI, stroke) due to the use of bromocriptine in the postpartum period. In fact, in 1995, this led to the withdrawal of FDA approval of bromocriptine for suppression of lactation in the postpartum period [16-18]. Due to these reports, there have been questions about the safety of bromocriptine therapy in PPCM.

James D Fett [33] expressed concerns over the fact that in the study conducted by Hilfiker-Kleiner et al. [30], some patients in one of the study groups experienced adverse events due to thrombosis and/embolism despite getting prophylactic anticoagulant. He also implied that the use of bromocriptine might have been responsible for such adverse outcomes by pointing out that no thromboembolism was observed in 99 subjects of the IPAC study (10) who did not receive bromocriptine. However, Hilfiker-Kleiner et al. [34] argued back that a recent study on PPCM [35] showed that 6.8 % of PPCM patients irrespective of treatment with or without bromocriptine had experienced a thromboembolic event. They also highlighted that all the thromboembolic adverse events reported in their study occurred weeks after cessation of bromocriptine treatment, and hence, argued that the thromboembolic events were not related to bromocriptine. According to them, the underlying disease process may have contributed to such adverse events [34].

It is important to note that in other studies [27, 29, 31] where prophylactic anticoagulation was used along with bromocriptine in PPCM patients, the number of prothrombotic adverse effects was unremarkable. Therefore, prophylactic anticoagulation use might be an effective strategy to reduce the risk of procoagulant adverse effects in PPCM patients taking bromocriptine. However, more studies are required before reaching any conclusion regarding this.

In 2017, Mattia Arrigo et al. [36] proposed the BOARD regimen for the treatment of PPCM. In this regimen, they included bromocriptine as a therapeutic option for all PPCM patients in addition to standard heart failure therapy. Figure 5 summarizes their recommendations. However, they made these recommendations based on the aforementioned study conducted by Hilfiker-Kleiner et al. [30] which was conducted in Germany, and the patient population of this study was overwhelmingly Caucasians. Therefore, more studies are required to assess the effectiveness of the BOARD regimen in treating PPCM patients of diverse ethnic and regional backgrounds.

Figure 5: The ‘BOARD’ regimen. MRA = Mineralocorticoid receptor antagonist, SBP = Systolic blood pressure. (Adapted from ‘Bromocriptine for the treatment of peripartum cardiomyopathy: welcome on BOARD) [58]

Funding: The author(s) received no financial support for the research, authorship, and/or publication of this article.