Genetics of Peripartum Cardiomyopathy: Current Knowledge, Future Directions and Clinical Implications

Abstract

Peripartum cardiomyopathy (PPCM) is a condition in which heart failure and systolic dysfunction occur late in pregnancy or within months following delivery. Over the last decade, genetic advances in heritable cardiomyopathy have provided new insights into the role of genetics in PPCM. In this review, we summarise current knowledge of the genetics of PPCM and potential avenues for further research, including the role of molecular chaperone mutations in PPCM. Evidence supporting a genetic basis for PPCM has emanated from observations of familial disease, overlap with familial dilated cardiomyopathy, and sequencing studies of PPCM cohorts. Approximately 20% of PPCM patients screened for cardiomyopathy genes have an identified pathogenic mutation, with TTN truncations most commonly implicated. As a stress-associated condition, PPCM may be modulated by molecular chaperones such as heat shock proteins (Hsps). Recent studies have led to the identification of Hsp mutations in a PPCM model, suggesting that variation in these stress-response genes may contribute to PPCM pathogenesis. Although some Hsp genes have been implicated in dilated cardiomyopathy, their roles in PPCM remain to be determined. Additional areas of future investigation may include the delineation of genotype-phenotype correlations and the screening of newly-identified cardiomyopathy genes for their roles in PPCM. Nevertheless, these findings suggest that the construction of a family history may be advised in the management of PPCM and that genetic testing should be considered. A better understanding of the genetics of PPCM holds the potential to improve treatment, prognosis, and family management.

Peripartum cardiomyopathy: a global effort to find the cause and cure for the rare and little understood disease

“…Goli et al (2021) identified 70 mutations in 12 genes from PPCM sampling. Another recent study found 21 genes were associated with cardiomyocytes that contribute to the genetic predisposition of PPCM patients (Spracklen et al 2021). Some of these gene mutations were also reported by Ware et al (2016) who constructed sequencing libraries of 43 genes and identified 26 truncating variants in 8 genes that were associated with dilated cardiomyopathy.…”

KLF13 Loss‐of‐Function Mutations Underlying Familial Dilated Cardiomyopathy

“…However, peripartum cardiomyopathy has been reported as a part of familial DCM, 89 and aggregating evidence has demonstrated the strong genetic basis of familial peripartum cardiomyopathy. 90 , 91 Factually, in roughly 20% of patients with peripartum DCM, screening for cardiomyopathy‐causative genes reveals pathogenic mutations, with TTN truncations most commonly implicated, occurring in approximately 10% of patients with peripartum DCM. 91 , 92 Hence, it is the right time to offer genetic testing to patients with peripartum DCM, 93 and referral for genetic testing should be considered if there is a positive family history of cardiomyopathy or sudden cardiac death.…”

State‐of‐the‐art document on optimal contemporary management of cardiomyopathies

“…Peripartum cardiomyopathy (PPCM) is defined as HFrEF (LVEF <45%) occurring within the last month before or 6 months after delivery in women without previous heart disease. 36,37 [37][38][39] Therefore, genetic testing is recommended in patients with PPCM, particularly in cases of familial history of cardiomyopathy. 1,37 Patients often display severe HF and a markedly reduced LVEF <35% with right ventricular (RV) involvement.…”