Rare variant mutations in pregnancy-associated or peripartum cardiomyopathy

Discussion

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.

Conclusion:

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.