Peripartum, Dilated Cardiomyopathies May Share Specific Gene Variants, Says Study

Deborah Brauser

January 07, 2016

BOSTON, MA — Mutations in the TTN gene, which are commonly found in idiopathic dilated cardiomyopathy, also seem common in peripartum cardiomyopathy—which may finally help explain why the latter condition occurs, new research suggests[1].

The study showed that 15% of 172 women with peripartum cardiomyopathy had 26 truncating variants in eight genes, which was similar to the 17% prevalence found in 332 patients with dilated cardiomyopathy. The prevalence for this line of variants was only 4.7% in a healthy cohort of almost 61,000 individuals.

Among the 26 variants found, 65% occurred in TTN, suggesting that "many of these truncating variants lead to a strong genetic disposition to peripartum cardiomyopathy," write the researchers, led by Dr James S Ware (Harvard Medical School, Boston, MA).

They note that there have long been questions surrounding why heart failure during pregnancy or soon after delivery occurs in certain women and that the findings suggest that the two cardiomyopathies have a shared mechanism.

"The results, which came as a surprise to us, are saying that problems with the muscle machinery are in part impeded in this disease. And we should think about how this works and whether we can devise medications that target that," principal investigator Dr Zoltan Arany (University of Pennsylvania, Philadelphia) told heartwire from Medscape. He added that the results are also a big step in potentially helping to diagnose patients.

"It could be that women who have these mutations do worse down the line than women who don't. And that's in our cross hairs to where we'd like to go," said Arany. "We don't yet have the data to make firm recommendations along those lines, but that's what we're thinking about and working toward."

The findings were published online January 6, 2016 in the New England Journal of Medicine.

Unknown Cause

In the US and Europe, the incidence of peripartum cardiomyopathy is between one in 1000 and one in 4000. However, countries such as Nigeria and Haiti have a higher incidence rate, averaging one in 100 to one in 300. Yet the cause of the condition has remained unknown.

The TTN gene "encodes the sarcomere protein titin," explain the investigators. "Up to 25% of patients with familial dilated cardiomyopathy and 18% of those with sporadic dilated cardiomyopathy harbor deleterious truncating variants . . . in TTN."

For the study, DNA was sequenced from the 172 participants with peripartum cardiomyopathy (mean age 31 years) to examine the 43 genes, along with their variants, that have most been associated with dilated cardiomyopathy. A total of 55 of the women were recruited from Pennsylvania, Germany, and Japan. The remainder were cohorts from the Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC-2) study (n=34) and the Investigations in Pregnancy Associated Cardiomyopathy (IPAC) study (n=83).

A comparison group of patients with dilated cardiomyopathy was recruited from London. In addition, data were examined from the Exome Aggregation Consortium and the Exome Variant Server.

First Answers

Overall, "the burden of genetic variants that were found in the women with peripartum cardiomyopathy resembled that found in patients with dilated cardiomyopathy," write the investigators.

"We can't necessarily extrapolate that all women with these variants will develop peripartum cardiomyopathy. But at least 15% and probably more will," added Arany. "For the first time, we have an explanation for a subset of these women that is quite novel."

In subgroup analyses of the IPAC cohort, 15 had truncating variants and 11 had truncating variants in TNN. Those in this latter group had a significantly lower ejection fraction at 1-year follow-up (P=0.005). However, only one member had hypertension, which has been linked in the past to cardiomyopathy.

In the full study population, there were no significant differences in truncating variants between those who did and did not have a family history of any type of cardiomyopathy.

"Since a gene-based diagnosis is clinically available" for dilated cardiomyopathy, the researchers note that using the same genetic diagnosis is plausible for peripartum cardiomyopathy "with similar sensitivity and specificity."

However, they note that further study is needed.

"There are currently no treatments for peripartum cardiomyopathy. While it's of interest to be able to categorize the disease into those women who have this genetic predisposition vs those who do not, we can't currently treat them differently," said Arany. "But down the line when we do have treatments, because there's plenty of research going along those lines, this is something we would want to know."

Arany added that there are exciting days ahead. "The field of peripartum cardiomyopathy, of understanding the disease, has been a bit of a black hole for a long time. But this, along with other research, is really breaking the door open," he said.

The study was funded by grants from the National Institutes of Health, the Fondation Leducq, the National Institute for Health Research Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London, Regenerative Biology and Reconstructive Therapies (REBIRTH) 2 Cluster of Excellence, Bundesministerium für Bildung und Forschung, and the Howard Hughes Medical Institute. Ware and Arany report no relevant financial relationships. Disclosures for the coauthors are listed on the journal website.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.