Effect of Bromocriptine in Dilated Cardiomyopathy in Women of Reproductive Age: A Hospital-Based Randomized Open Label Placebo-controlled Clinical Trial

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).