Bromocriptine in Dilated Cardiomyopathy Among Women of Reproductive Age

Overview

Dilated cardiomyopathy (DCM) is a condition associated with left and /or right ventricular (LV) dilatation and systolic dysfunction without coronary artery disease or abnormal loading circumstances proportionate to the severity of LV impairment. It is one of the leading causes of heart failure in younger adults. About 35% of patients have genetic mutations affecting cytoskeletal, sarcomere, and nuclear envelope proteins while others are idiopathic and possibly complications of myocarditis. Recently, in patients with peripartum cardiomyopathy (PPCM)-a subtype of dilated cardiomyopathy, high levels of prolactin and its degradation by-products including a cleaved 16kDa N-terminal fragment have emerged as key factors in the pathophysiology. The 16kDa prolactin induces profound endothelial damage and subsequent cardiomyocyte dysfunction and hence heart failure. Bromocriptine has been studied as a potential treatment option and placebo-controlled studies have demonstrated its beneficial role in women with Peripartal cardiomyopathy (PPCM). However, prolactin level may also increase during menstrual cycles of reproductive-age women, which candidates the use of bromocriptine in women of all reproductive ages. The aim of this study is therefore to assess the potential effect of bromocriptine in dilated cardiomyopathy among women of reproductive age.

Background: Cardiovascular diseases (CVDs) are the leading cause of death globally. An estimated 17.9 million people died from CVDs in 2017, representing 32% of all global deaths. Over three quarters of the CVD deaths take place in low- and middle-income countries. In 2022, CVDs account for almost 12% of the total burden of disease ranking third behind cancer and musculoskeletal conditions(1). A systematic review conducted in Ethiopia found that the prevalence of CVD ranges from 7.2 to 24% (2,3). Recently, the pooled prevalence of cardiovascular disease (CVD) was 5% (95% CI: 3-8%) with higher prevalence in the population who visits hospitals, 8% (95% CI: 4-12%) compared to the general population, 2% (95% CI: 1-5%) (3). Dilated cardiomyopathy (DCM) is a condition associated with Left and or right ventricular (LV) dilatation and systolic dysfunction without coronary artery disease or abnormal loading circumstances proportionate to the severity of LV impairment (4-6). It is one of the leading causes of heart failure in younger adults, often requiring cardiac transplantation (7,8), and it is caused by various factors, including myocarditis, alcohol, drug, and metabolic disturbances (7,9). Hormonal factors including prolactin have recently been implicated to play a role in the development of DCM in women (10,11). About 35% of patients have genetic mutations affecting cytoskeletal, sarcomere, and nuclear envelope proteins while others are mainly idiopathic, including possibly complications of myocarditis (10-12). The prognosis depends on the severity and heart remodeling, with the worst outcomes in patients with low ejection fractions or severe diastolic dysfunction. DCM appears more common in men, than in women (12,13). However, a recent systematic review in Ethiopia indicates that there is no significant difference in the overall prevalence of CVD between males and females (3). Despite many progresses made in the past decades in the development of novel pharmacological treatments for HF, proper management of HF is still challenging and there remains a substantial unmet need in heart failure. In recent years, a number of contributory mechanisms have been recognized to initiate and propagate cardiomyopathy (11-13). Prolactin has been found to be elevated in some cases of cardiomyopathy specially in the cases of peripartal cardiomyopathy (10,11), and may contribute to the development and progression of the condition. In patients with peripartum cardiomyopathy (PPCM), high levels of the hormone prolactin and the production of a cleaved 16kDa N-terminal fragment of prolactin have emerged as potential key factors in the pathophysiology of PPCM. The 16kDa prolactin induces profound endothelial damage and subsequent cardiomyocyte dysfunction and full-length prolactin promotes inflammation in PPCM (11-14). Bromocriptine, a dopamine agonist that is primarily used to treat conditions such as Parkinson's disease, hyperprolactinemia, and acromegaly, has been investigated as a potential treatment option for Peripartal cardiomyopathy (PPCM), a form of DCM that occurs in the last month of pregnancy or up to five months postpartum (11,15). Clinical pilot studies showed the feasibility of bromocriptine in improving left ventricular (LV) recovery and clinical outcome (11,15-17). A recent multi-center randomized study comparing two different bromocriptine dosages (2.5 mg daily for one week vs. 5 mg daily for 2 weeks, followed by 2.5 mg daily for 6 weeks) in severe PPCM patients demonstrated an improved clinical outcome with high LV recovery rate at 6 months and with no mortality, no use of left ventricular assist device or heart transplantation (18,19). Consequently, bromocriptine is recommended for the treatment of pregnancy-related cardiomyopathy (PPCM) due to a significant increase in prolactin levels in these group of patients. In such patients, the benefit of bromocriptine may be attributed to its ability to reduce prolactin levels. We hypothesize that, prolactin levels may also increase in women with DCM (15,19,20)of reproductive-age, and bromocriptine could also be a good candidate to use in women of all reproductive ages with DCM. Moreover, prolactin-independent cytoprotective effects of bromocriptine demonstrated in various organs including the heart may also support our hypothesis that bromocriptine may provide clinical benefit in all women with DCM (21-23). Given the limited evidence to use of bromocriptine in DCM among women of reproductive age, further research is needed to fully understand whether or not bromocriptine improves clinical outcome compared to the standard treatment for heart failure in all or a subset of women. Therefore, this proposal aims to assess the potential benefit of bromocriptine in dilated cardiomyopathy among women of reproductive age. Thus, the study aims to provide a valuable information on the potential use of bromocriptine in women of reproductive age with DCM. If our hypothesis is confirmed, it may offer a good add-on treatment option that is also easily available for this population, and potentially improve treatment outcome and quality of life. Problem statement Heart failure (HF) is a progressively deteriorating medical condition that significantly reduces both patients' life expectancy and quality of life. Dilated cardiomyopathy (DCM) is one of the leading causes of heart failure in younger adults. Despite many progresses made in the past decades in the development of novel pharmacological treatments for HF, proper management of HF is still challenging and there remains a substantial unmet need in treating heart failure. Bromocriptine, an inhibiter of prolactin release by dopamine-D2-receptor, has been studied in the context of heart failure due to peripartal cardiomyopathy, and some studies have demonstrated its beneficial role in women with peripartum cardiomyopathy (PPCM) (15). As prolactin levels also increase in women of reproductive-age during menstrual cycle, bromocriptine could also be a good candidate to use in women of all reproductive ages and DCM. Although reports show a beneficial role of bromocriptine in improving the left ventricular function in some patients with heart failure, the results may not be applicable to a wide range of populations and patients due to various sources of variation between populations (15) . Thus, it would be relevant to conduct a rigorous clinical trial to assess the efficacy and safety of this treatment option in diverse populations like Ethiopians in terms of etiologies of heart failure. It has been established that the same dose of a medication is associated with considerable heterogeneity in pharmacokinetics (PK) and pharmacodynamic (PD) efficacy and toxicity across human populations (16,17,21,23,24). This inter-individual difference in drug response can be explained by pharmacogenetic variations or other factors such as variations in patients' age and weight, co-morbidity, lifestyle, co-medication, renal and liver function, unfavorable drug-drug interactions and poor compliance of patients (17,24). The pharmacokinetics (PK) of bromocriptine in heart failure patients, the inter-individual variability in PK and clinical response and associated sources of variations have not been investigated before. Thus, this study is also designed to investigate the effectiveness of bromocriptine in terms of efficacy and safety as well as the blood levels and PK of bromocriptine among women of reproductive age with DCM in Ethiopia.