Shared Genetic Predisposition Between Peripartum Cardiomyopathy and Idiopathic Dilated Cardiomyopathy

Peripartum cardiomyopathy shares genetic predisposition, TTN truncating variants, with both idiopathic and familial cardiomyopathy.

IMAC-2 and IPAC investigators (Intervention in Myocarditis and Acute Cardiomyopathy 2; Investigations in Pregnancy Associated Cardiomyopathy) have determined that peripartum cardiomyopathy shares a genetic predisposition with familial and sporadic idiopathic cardiomyopathy, according to data published in the New England Journal of Medicine.

Idiopathic dilated cardiomyopathy is caused by mutations in more than 40 genes, including TTN. Peripartum cardiomyopathy presents similarly in terms of clinical features: decreased systolic function, enlarged cardiac dimensions, and nonspecific histologic findings on biopsy.

Researchers sequenced 43 genes with variants that have been associated with dilated cardiomyopathy in 172 women with peripartum cardiomyopathy. They found 26 truncating variants in 8 genes among these women (15%), which was significantly higher than in a reference population of 60 706 (4.7%; P=1.3 x 10–7). However, this prevalence was similar to a cohort of patients with dilated cardimyopathy (55 of 332 patients [17%]; P=.81).TTN was identified as two-thirds of the truncating variants in 10% of patients and 1.4% in the reference population (P=2.7 x10–10), with nearly all of the variants located in the titin A-band.

At 1-year follow-up, researchers analyzed a subgroup of 83 women in the IPAC study who had peripartum cardiomyopathy and found TTN truncating variants were significantly correlated with a lower ejection fraction (P=.005). The same effect was seen in patients with dilated cardiomyopathy. Conversely, 34 women in a subgroup of the IMAC-2 study, ejection fraction was not significantly different among the 3 women with TTN truncating variants compared with those without these variants.

“Preeclampsia and gestational hypertension are strong risk factors for peripartum cardiomyopathy, but there has been controversy as to whether cardiomyopathy that is associated with hypertension may represent a separate disease from cardiomyopathy in the absence of hypertensive disorders,” researchers wrote.

In fact, only 4 out of 15 women with truncating variants in a well-characterized IPAC cohort had a form of hypertension (chronic or gestational) and among the 11 with TTN truncating variants, only 1 had hypertension.

Preeclampsia and hypertension occur more often in women of African descent, according to previous research, but none of the 7 women in the study who were of said descent with a TTN truncating variant had a hypertensive disorder. Among women without hypertension, the burden of truncating TTN variants was 10 times as high compared with women who had hypertension (23% vs 2%; P=.005).

“Previous studies have shown that peripartum hormonal changes can pose a vascular insult to the heart and trigger peripartum cardiomyopathy,” they wrote. “What predisposes the development of this disease in only a small subgroup of women in this context remains unclear.”

Researchers concluded, “…defining the mechanistic interaction between truncations in TTN and late gestational antivascular insults will probably lead to further understanding of both peripartum cardiomyopathy and dilated cardiomyopathy.”


Ware JS, Li Jian, Mazaika E, et al; for the IMAC-2 and IPAC Investigators. Shared genetic predisposition in peripartum and dilated cardiomyopathies. N Engl J Med. 2016;doi:10.1056.NEJMoa1505517.