Peripartum cardiomyopathy (PPCM) is a devastating illness afflicting new mothers worldwide. Despite being relatively uncommon in many areas of the world, PPCM is nonetheless an important cause of morbidity and mortality in new mothers. For this reason, it has received welcome attention by investigators in the past decade, with numerous reports and recent general reviewsCitation[1–6]. PPCM represents a syndrome of pregnancy-associated cardiomyopathy (PACM) Citation[7] with multiple antecedents and complex biopathological processes. Whatever the precipitating factor(s) may be, immune system dysfunction with evolution to an autoimmune cardiomyopathy seems highly likely Citation[5,6,8–11]. At the present time, two hypotheses of etiology are foremost: pregnancy-associated hormonal changes, specifically the role of prolactin (PRL); and viral infection.
Pregnancy-associated hormonal changes
In the PRL theory, proposed and advanced by Sliwa and Hilfiker-Kleiner Citation[12,13], activated cathepsin-D cleaves normal 23-kDa PRL, resulting in a purported cardiotoxic 16-kDa PRL. In their pilot study, impressive gains in systolic function at 6 months were reported for many of the ten women receiving bromocriptine and conventional heart failure treatment compared with ten control mothers receiving conventional treatment alone. The appropriate balance and caution in exploring this important hypothesis are provided in the recent editorial by Elkayam and Goland, emphasizing the need for “a large, well-designed, prospective study” Citation[14]. This editorial also reports a trial of bromocriptine in two PPCM patients without benefit.
Given the number of PPCM patients who recover to left ventricular ejection fraction (LVEF) more than 0.50 with contemporary evidence-based treatment without bromocriptine, the challenge will be to devise a study with sufficient power to give valid results Citation[15–17]. It is also difficult to devise randomly assigned, double-blinded trials owing to the need to assure adequate newborn nutrition for those to whom breast milk will not be available as a result of PRL inhibition.
Analysis of individual patients from these investigator reports with limited testing to date has demonstrated that not all PPCM mothers test positive for cathepsin-D activation and detectable 16-kDa PRL Citation[12–14]; not all mothers tested have shown elevated plasma levels of PRL at the time of diagnosis (four out of ten in each group had time-of-diagnosis of PPCM plasma levels of PRL less than 25 µg/l, levels seen in nonpregnant, nonlactating women Citation[18]); not all mothers tested have documented suppression of PRL; and not all mothers treated with bromocriptine have shown improvement in LVEF in the first 6 months postdiagnosis. These are essential details that must be explored in this challenging hypothesis that Sliwa et al. have advanced Citation[13].
In subsequent research, it may be best to conduct trials with bromocriptine treatment in PPCM mothers who:
• Demonstrate serum cathepsin-D activation
• Test positive for the presence of serum 16-kDa PRL
• Accept lactation suppression and the inability to breastfeed
• Have assured alternative nutrition for their newborns
In addition, because almost all PPCM patients with diagnostic LVEF of 0.35 or more go on to recovery with evidence-based conventional treatment of diuretics, ACE inhibitors and b-blockade Citation[17,19], one may wish to limit the use of PRL inhibition treatment to those with a LVEF of less than 0.35 at diagnosis. Arbitrary use of bromocriptine outside of a research protocol will not answer the lingering questions and may subject patients to as yet unidentified risks. Additional research also needs to continue on the evidence that ACE-inhibitors and β-blockers help to correct the immune system dysfunction that occurs with PPCM/PACM, quite apart from their hemodynamic benefits Citation[20–23].
Viral infection
It is clear in both humans and experimental animals that infection with cardiotropic viruses can result in dilated cardiomyopathy and heart failure Citation[11,24–26]. Evidence supporting a role for viral infection in PPCM stems from case reports documenting viral positivity by IgM serum antibodies and PCR viral genomes in serum and/or cardiomyocytes Citation[27–30]. Viruses involved include adenovirus, coxsackievirus B (enterovirus), cytomegalovirus, E-B virus, hepatitis C virus, human herpesvirus 6, influenza virus A/B and parvovirus B19 Citation[24–42]. Further documentation will require systematic testing of peripheral blood in a large series of prospectively identified PPCM mothers, as suggested in an earlier publication Citation[29].
It is this group of mothers with PACM in whom intravenous immunoglobulin may still hold some promise for effective treatment and warrant additional trials; most particularly, the nonresponders to conventional evidence-based treatments, including those who have fulminant disease with imminent mortality Citation[30,43–46].
For at least some cardiotropic viruses, presence in the myocardium does not appear to be sufficient to confirm a causal role. This may particularly be the case for parvovirus B19 Citation[47]. Additional evidence of replication and myocardial viral load may be necessary to confirm a pathogenic role Citation[48]. It also remains to be seen if the additional presence of cellular infiltrate with a lymphocytic myocarditis or inflammatory cardiomyopathy could help to differentiate pathogenesis from the nonpathogenic coincidental presence of viral particles.
Antecedent disease
There appears to be a group of PPCM mothers who may have had asymptomatic systolic dysfunction (ASD) before the index pregnancy in which PPCM was diagnosed Citation[49,50]. Unless an echocardiogram had been carried out previously there would be no way of knowing this. Aggravation of antecedent ASD with current pregnancy-associated heart failure could occur from unrecognized preceding pregnancy PPCM, unrecognized familial dilated cardiomyopathy or other forms of cardiomyopathy, or unrecognized nonpregnancy-associated antecedent viral cardiomyopathy.
Other cardiac stressors
There are multiple cardiac stressors that may or may not play a causative role, but may tip the balance into overt heart failure. These include: pregnancy-induced hypertension, chronic hypertension, toxemia of pregnancy, anemia, multiple gestations, prolonged tocolytic therapy, hormonal manipulations with assisted reproductive technologies and oxidative stress. Each merits additional investigation.
Profiling PPCM patients
Whatever the role of the aforementioned factors may be, it may be helpful to attempt to understand and classify PPCM patients on the basis of their:
• Autoimmune antibody profiles (particularly cardiac β-1-adrenoreceptor and cardiac myosin heavy-chain autoantibodies)
• Pro- and anti-inflammatory cytokine and chemokine profiles
• C-reactive protein levels
• B-type natriuretic peptide levels Citation[9,10,51–58].
Genetics may play a very important role in determining cytokine and chemokine imbalances, and thus subsequent susceptibilities to immune system dysfunction Citation[9]. It should not be overlooked that two African-origin PPCM populations (Soweto [South Africa] and Haiti) have demonstrated significantly reduced plasma levels of the cytokine TGF-b, important in fibrosis, inflammation and combating viral infections Citation[56,59–61]. This could factor into the increased incidence of PPCM in African-origin populations Citation[62,63].
Post-PPCM pregnancies
After concern for survival and recovery, one of the most important issues facing PPCM mothers is the question of the safety of a post-PPCM pregnancy. Studies concerning this issue are in agreement that the risk of relapse of heart failure is high for those who have not reached apparent recovery levels of systolic heart function Citation[64–67]. Only one study has prospectively followed PPCM mothers through a subsequent pregnancy, suggesting that the lowest risk for relapse attends those who have recovered to a LVEF of at least 0.55, maintain that recovery level after safe discontinuation of heart failure medications and demonstrate adequate contractile reserve on stress testing Citation[68].
The Peripartum Cardiomyopathy Network, a NIH-funded North American study of PPCM linking more than 30 medical centers, is now poised to address these issues [McNamara D, Pers. Comm.]. Focus on PPCM issues in the past decade have brought us to the position of potentially making breakthrough discoveries that will markedly improve prospects for PPCM mothers all over the world.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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