Presented by: Pr Philippe Charron, Referral center for cardiac hereditary diseases, Ambroise Paré Hospital and Versailles Saint Quentin University, Paris Ouest, France
Authors: Ware JS(1), Li J, Mazaika E, Yasso CM, DeSouza T, Cappola TP, Tsai EJ, Hilfiker-Kleiner D, Kamiya CA, Mazzarotto F, Cook SA, Halder I, Prasad SK, Pisarcik J, Hanley-Yanez K, Alharethi R, Damp J, Hsich E, Elkayam U, Sheppard R, Kealey A, Alexis J, Ramani G, Safirstein J, Boehmer J, Pauly DF, Wittstein IS, Thohan V, Zucker MJ, Liu P, Gorcsan J 3rd, McNamara DM, Seidman CE, Seidman JG, Arany Z; IMAC-2 and IPAC InvestigatorsN Engl J Med. 2016 Jan 21;374(3):233-41.
Peripartum cardiomyopathy (PPCM) is characterized by systolic dysfunction that occurs in late pregnancy or early postpartum. Several risk factors have been identified including advanced maternal age, history of preeclampsia, multiparity and multiple gestation. However PPCM pathophysiology remains poorely understood. There is also no clear explanation for why heart failure develops only in a small subgroup of women. Some recent data support the role for genetic factors in PPCM that may share some determinants with Dilated cardiomyopathy (DCM). This hypothesis was further studied in the present paper.
To search for and describe the pathogenic mutations that may be responsible for PPCM and compare the figures with those coming from a DCM population.
The authors analyzed 172 women with peripartum cardiomyopathy (from 6 independent groups including IMAC-2 and IPAC networks), and sequenced 43 genes with variants that have been previously associated with dilated cardiomyopathy. They compared the prevalence of different variant types (nonsense, frameshift, and splicing) in these women with the prevalence of such variants in 332 persons with dilated cardiomyopathy and with population controls (ExAC and EVS consortia, related to exome analysis of ~60,000 and ~6,500 persons respectively).
Authors identified 26 distinct, rare truncating variants in eight genes among women with peripartum cardiomyopathy. The prevalence of truncating variants (26 in 172 [15%]) was significantly higher than that in a reference population of 60,706 persons (4.7%, P=1.3×10-7) but was similar to that in a cohort of patients with dilated cardiomyopathy (55 of 332 patients [17%], P=0.81). Two thirds of identified truncating variants were in titin gene (TTN), as seen in 10% of the patients and in 1.4% of the reference population (P=2.7×10-10); almost all TTN variants were located in the titin A-band. Seven of the TTN truncating variants were previously reported in patients with idiopathic dilated cardiomyopathy. In a clinically well-characterized cohort of 83 women with peripartum cardiomyopathy, the presence of TTN truncating variants was significantly correlated with a lower ejection fraction at 1-year follow-up (P=0.005).
The authors observed that the distribution of truncating variants in a large series of women with peripartum cardiomyopathy was remarkably similar to that found in patients with idiopathic dilated cardiomyopathy. TTN truncating variants were the most prevalent genetic predisposition in each disorder.
Some studies previously suggested that pathophysiology of PPCM may partially overlap with DCM and may have a genetic predisposition. A substantial number of DCM families include some female patients with “PPCM”. Alternatively, the screening of relatives of PPCM patients may identify a number of DCM patients. Occasionnaly, a mutation screening in PPCM patients may identify some pathogenic mutations in genes responsible for conventional DCM such as MYH7 and TNNC1 genes. These reports were however quite rare. Finally a genome-wide association study (GWAS) identified a locus on chromosome 12 (near PTHLH gene) that predispose to PPCM.
The present study of Ware et al. provides new data strongly supporting a role for genetic factors in PPCM. Truncating variants in eight genes were identified in about 15% of PPCM women versus about 5% in a control population (P=1.3×10-7), Furthermore the figure was very similar to that observed in a DCM population (17%) with the same method and panel for sequencing. Interestingly titin gene (TTN) was the most prevalent mutated gene (two-third of genetic varianst) in PPCM (10%) as well as in the DCM population (TTN truncating variants were previously identified in up to 25% of familial forms of DCM and 18% of sporadic forms of DCM). Vast majority of TTN truncations (14/17) are located in the region encoding the A-band, as in DCM, and several TTN truncations found in PPCM (7/17) were previously described in DCM patients. Therefore PPCM patients cleary share a genetic predisposition with DCM. Apart from the better knowledge of the pathophysiology of PPCM, this finding may have important consequences for clinical practice since could support a systematic family screening and follow-up of relatives in case of a diagnosis of PPCM.
Further studies are however required to clarify the full consequences of these results. Since truncation variants are also observed in a general control population, although significantly less frequent, the penetrance of mutations may be partial, with complex determinants of cardiac expression. For example there might be some additional environmental or genetic factors that explain why age at onset of DCM with TTN truncations is about 65 years as compared to 28 years in PPCM women. It is also not clear why women with PPCM recover systolic dysfunction more frequently than do women with DCM. Finally only truncating variants were significantly more frequent on PPCM than in a control population regarding the panel of genes analyzed by the authors. When missense probable pathogenic mutations are considered, then prevalence of such missense variants are high in women with PPCM (about 1 per person) and not different from the burden found a control population (ExAc cohort).
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2. Rare variant mutations in pregnancy-associated or peripartum cardiomyopathy. Morales A, Painter T, Li R, Siegfried JD, Li D, Norton N, Hershberger RE. Circulation. 2010;121(20):2176-82.
3. Benjamin D. Horne; Kismet D. Rasmusson; Rami Alharethi; Deborah Budge; Kimberly D. Brunisholz; Torri Metz; John F. Carlquist; Jennifer J. Connolly; T. Flint Porter; Donald L. Lappé; Joseph B. Muhlestein; Robert Silver MD; Josef Stehlik; James J. Park; Heidi T. May; Tami L. Bair; Jeffrey L. Anderson; Dale G. Renlund; Abdallah G. Kfoury. Genome-wide Significance and Replication of the Chromosome 12p11.22 Locus Near the PTHLH Gene for Peripartum Cardiomyopathy. Genome-wide Significance and Replication of the Chromosome 12p11.22 Locus Near the PTHLH Gene for Peripartum Cardiomyopathy. Circ Cardiovasc Genet. 2011 Aug 1;4(4):359-66.
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