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.

Keywords: chaperones; genetic cardiomyopathy; heat shock proteins; peripartum cardiomyopathy.

Figure 1

Known and possible mechanisms of peripartum cardiomyopathy (PPCM) pathophysiology. kDa, kilodalton; sFLT1, soluble fms-like tyrosine kinase-1.

Figure 2

Localisation and function of PPCM-associated genes in the cardiomyocyte. The majority of PPCM genes, including Titin (TTN), comprise the cardiac sarcomere, but mutations affecting numerous other aspects of cardiomyocyte function have been implicated in PPCM pathogenesis.

Figure 3

Proportion of reported PPCM patients with pathogenic mutations. Other sarcomeric genes: MYBPC3, MYH6, MYH7, TNNC1, TNNT2, TPM1; X-linked genes: DMD, LAMP2; Other genes: DSP, PSEN2, VCL.

Figure 4

Distribution of genes associated with PPCM to date. Countries in which genetic investigations of PPCM patient(s) have been conducted are indicated in blue. The number of pathogenic mutations identified in each gene is indicated in parentheses. Three pathogenic MYH7 mutations and seven SCN5A mutations are not included as the countries of origin could not be determined.

Figure 5

Functions of molecular chaperones in regulating cardiomyocyte protein quality. The major molecular chaperone families and their roles in the maintenance of cardiomyocyte protein quality control are illustrated. Hsp70, Hsp90, sHsp and Hsp40 are particularly important in protein folding, while Hsp60 facilitates protein translocation and BAG3 facilitates the degradation of misfolded proteins.