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Peripartum cardiomyopathy (PPCM) is recognized as a distinct form of heart failure, with highly variable clinical course. Recently published (1) position statement from the Heart Failure Association of the ESC WG on peripartum cardiomyopathy provides new definition of PPCM as “an idiopathic cardiomyopathy presenting with heart failure secondary to left ventricular (LV) systolic dysfunction towards the end of pregnancy or in the months following delivery, where no other cause of heart failure is found”. Therefore, the diagnosis of PPCM is ‘the diagnosis of exclusion’. The LV may not be dilated but the LVEF is nearly always reduced below 45%”. Sliwa et al. (1) also emphasized that the time frame (development of the disease during the last month of pregnancy or within 5 months of delivery) recognized as important part of definition of PPCM is arbitrary and may lead to under-diagnosis of PPCM. Of note, in 2005 Elkayam et al. published 23 cases of early pregnancy-associated heart failure (PACM) with the onset of idiopathic heart failure as early as in week 17 and found them to be clinically indistinguishable from classic PPCM (2). Obviously, these two are undistinguishable from dilated cardiomyopathy (DCM).
Though PPCM may be reversible and spontaneous recovery is often reported, rapid hemodynamic compromise leading to the requirement of ventricular assist devices within days or urgent heart transplantation may occur. PPCM constitutes the most frequent factor contributing to pregnancy-related death. Risk factors include: maternal age over 30 years, multiple gestation, multiparity, preeclampsia and toxemia of pregnancy (3, 4). Whereas cause(s) of PPCM are not known, the role of higher cardiac demand, immune system dysfunction/autoimmune response, myocarditis, dietary deficiencies, oxidative stress and genetic origin were all suggested (4, 5). Recently, a major focus has been placed on the role of prolactin, which, as a result of aberrant proteolytic cleavage probably caused by an unbalanced oxidative stress, is the source of pathogenic anti-angiogenic, pro-apoptotic and pro-inflammatory 16-kDa subform (6). This hypothesis has direct clinical relevance pointing to blockade of prolactin by bromocriptine as a therapeutic option, which indeed appeared successful in pilot trials 7. Given this background the results of Morales et al. (8), which bring up the issue of genetic causes of PPCM, are worth commenting.
The authors hypothesized that mutations in genes linked with DCM may also account for some PPCM/PACM cases and employed their DCM patient database to test this. The database comprised 4110 women with idiopathic cardiomyopathy from 520 families.
Forty two unrelated cases of PPCM/PACM (23 with familial clustering) were identified. Nineteen patients were screened for mutations by sequencing of exon and exon-intron boundaries in 14 DCM genes. Six (32%) non-synonymous mutations all located in different genes were found. Five of them (in MYH7, TNNT2, MYH6, SCN5A and PSEN2 genes) were associated with PPCM, while one (in MYBPC3) was present in a PACM subject. Three patients with PPCM and one patient with PACM inherited their mutations. The pathogenicity was validated by excluding the presence of mutations among 246-413 control subjects.
In the same issue of Circulation van Spaendonck-Zwarts et al. (9) performed the search for PPCM cases in their database of 90 families with DCM. Five families had members with PPCM (6%). Further, 10 independent PPCM cases were also studied including 3 patients who did not fully recover. Their first-degree family members, previously undiagnosed, were examined and DCM was found within all 3 of these families. Moreover, one mutation (in the TNNC1 gene) segregating with disease was found in a DCM family with a PPCM patient.
Thus, the studies by Morales et al. and van Spaendonck-Zwarts et al. both describe an association of genetic factors with PPCM. It appears that the same mutations which are responsible for DCM may play, at least in a subset of patients, a pathogenic role in PPCM.
An important clinical message from these results is that family history in PPCM may be revealing and should be elicited (4), and evidence for the genetic causation should be sought in PPCM with the aim of early diagnosis of affected relatives similarly as it is done in DCM. This, as the Morales et al. (8) advise, should include analysis of 3- to 4-generation family pedigrees along with thorough clinical examination of first-degree family members. Although general genetic testing is not recommended as routine (1), it can be performed as part of research projects. DCM genetic background is highly heterogeneous, and PPCM has several unique features, therefore variants in genes not known in DCM may underlie disease activation. However, performing genome wide and candidate gene association studies with modern high-throughput techniques like high-density arrays may bring us closer to understanding the genetic factors behind this condition (10).
The studies by Morales et al. (8) and van Spaendonck-Zwarts et al. (9) raise interesting questions regarding pathogenesis and treatment of PPCM. In the context of emerging central role of 16-kDa cleavage product of prolactin in PPCM with antiangiogenic and proapoptotic activities (6) it would be interesting to know whether there are any differences in outcome between groups of patients with identified variants associated with development of PPCM and other groups with unknown etiology of the disease. It could well be speculated that the disease development in patients with genetic defect(s) depends mainly on factors like volume overload rather than prolactin, which could make bromocriptine treatment ineffective.
The high incidence of PPCM in certain communities is suggestive of distinct environmental factors playing a major role in the development of PPCM. This is supported by earlier studies showing myocarditis (11, 12) and abnormal immune response (13, 14) in PPCM. Ultrastructural differences might also exist. Recently, our group analyzed myocardium of PPCM patient and 3 other patients with fulminant heart failure not related to PPCM serving as a control group - two with myocarditis and one with DCM. PPCM subject’s myocardial tissue demonstrated endothelial cell apoptosis as well as remodelling of small capillaries leading to impairment of microcirculation, whereas no such alterations were present in the control group suggesting pathogenic uniqueness of PPCM (15). In the context of discussed findings (8, 9) it would clearly be interesting to compare the role of these factors in PPCM/PACM with and without DCM associated genetic defects. Finally, it should also be noted that the discussed studies had some limitations, the most obvious being the relatively small number of women with DCM and/or PPCM/PACM.
In particular, Morales et al. spent 15 years building their DCM patient database and ended up with only 42 unrelated cases of PPCM/PACM, of which 19 were screened for mutations in 14 DCM genes. Also, the screening performed could be regarded as incomplete since only 14 out of more than 30 known DCM genes were selected for analysis and even those were not screened in all patients. However, this may suggest that many more mutations are still to be detected in this cohort.
In conclusion, the findings of Morales et al. (8) and van Spaendonck-Zwarts et al. (9) provide an interesting new perspective on PPCM/PACM with implications for both the basic research and clinical practice.
Michal Saj, M. Sc,
Laboratory of Molecular Biology, Institute of Cardiology, Warsaw
Assoc. Prof. Rafal Ploski, M.D. PhD,
Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw
Assoc. Prof. Zofia T. Bilinska, M.D. PhD,
Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology Warsaw, Poland