Pregnancy results in a relative immunocompromised state. A reasonable hypothesis regarding the development of PPCM is that a decreased humoral and cellular immunity predisposes to myocarditis. Infection was identified as a potential causal mechanism based on small retrospective studies. In patients diagnosed with PPCM, cardiac biopsies reveal histologic evidence of viral infection. In one study of 26 patients with PPCM, a third were positive for various viruses, although only two-thirds of that group had evidence of myocarditis on biopsy.⁴ In other studies where myocardial biopsy was performed, varying rates of myocarditis are observed.⁵ One study found evidence of viral myocarditis in 14 of 18 patients.⁶ Another found evidence of myocarditis in less than 10%.⁷ Overall, evidence of myocarditis in patients diagnosed with PPCM ranges from 0% to 100%.⁵ Molecular tests for viral strains in PPCM revealed viral genomes in 30%, which were in turn associated with histologic inflammation.⁴ Interestingly, another study found approximately 30% of healthy pregnant patients had viral genomes on molecular testing.⁵ The role of an underlying or inciting viral process in the development of PPCM is unclear, and the evidence currently has mixed conclusions.^2,3

A genetic basis for disease has been suggested. Case reports detail incidences of multiple individuals of the same family diagnosed with PPCM. Genetic predisposition to the development of viral myocarditis has been suggested; however, it is unclear if viral infection and consequent myocarditis is the mechanism of disease.² Although no single molecular genetic association has been discovered to date, a recent study showed that, as in idiopathic dilated cardiomyopathy, certain genetic variants are more common in women with PPCM and may even predict the severity of the disease.⁸

Excessive prolactin production, an endogenous hormone with multiple biologic functions, is another area of investigation in the pathogenesis of PPCM.⁹ Theoretically, a deficiency of the cardiac protein STAT-3 leads to cleavage of prolactin into an isoform that has antiangiogenic and proapoptotic properties. In mice, knockout of the STAT-3 gene leads to an increased incidence of PPCM. Treatment of STAT-3-deficient mice with bromocriptine, an inhibitor of prolactin secretion, prevented PPCM.³ There are case reports discussing successful treatment of PPCM with bromocriptine.^10,11,12,13 In a study of women with newly diagnosed PPCM randomized to receive standard of care heart failure treatment (SHFT) or bromocriptine in addition to SHFT, bromocriptine’s use was associated with decreased morbidity and mortality.¹⁴ Another retrospective cohort study found improved outcomes among women with a history of PPCM treated with bromocriptine with subsequent pregnancies.¹⁵ To date, no large randomized controlled trials exist to validate the use of bromocriptine in this context, and it remains an area of active research.

A dysregulated inflammatory process is another theoretical pathophysiologic etiology underlying PPCM.³ The increased workload of the heart during pregnancy potentially leads to proinflammatory cytokine release and resultant left ventricular failure. Cytokines are known to have direct effects on the cardiovascular system including promotion of oxidative stress, cardiac structure, myocyte function, endothelial injury, and activation of cardiac myocyte apoptotic pathways. Inflammatory cytokines have been shown to result in decreased inotropy and cardiac contractility. Persistently elevated levels of these mediators caused by the increased cardiovascular demand of pregnancy may result in left ventricular remodeling and dysfunction in certain individuals. Similar to the other proposed mechanisms of disease, the role of cytokines is unclear.

An abnormal immune response is yet another possible etiology. The immune system is altered during pregnancy and is globally reduced. Autoantibodies have been discovered in patients diagnosed with PPCM. One study found autoantibodies in over 50% of PPCM patients.¹⁶ Multiple antibodies have been discovered with targets including myosin heavy and light chains, cardiac actin, beta-1 adrenergic receptors, and other cardiac tissue-specific proteins.⁵ A proposed mechanism is that fetal cells enter the maternal circulation, deposit in cardiac tissue, and trigger an autoimmune response.² It is still unclear whether the antibodies discovered in PPCM patients cause disease, but if implicated it may offer potential targeted therapy.