Research Identifies Genetic Variants that Might Predispose Pregnant Women to Rare Heart Condition

Zoltan Arany, MD, PhD

A National Institutes of Health-funded study is shedding light on a group of genetic variants that could help identify otherwise healthy women at risk of a rare cardiovascular condition that affects pregnant women.

Results of the Penn Medicine-led research build on previous studies examining genetic variants in women with peripartum cardiomyopathy (PPCM) and researchers suggest results could help guide clinical decision-making for these patients.

"This study provides the first extensive genetic and phenotype landscape of PPCM and has major implications for understanding how PPCM and DCM are related to each other," said Zoltan Arany, MD, PHD, Professor of Cardiology in the Perelman School of Medicine at the University of Pennsylvania, in a statement. "It shows that predisposition to heart failure is an important risk factor for PPCM, suggesting that approaches being developed for DCM may also apply to patients with PPCM."

Building on a previous study he led that suggested that some genetic mutations predispose women, which was published in NEJM in 2016, Arany sought to further establish genetic variants to help identify patients at risk of PPCM. With these studies identifying truncating loss-of-function (LOF) variants in the gene TTN of women with PPCM, investigators designed the current study to identify novel genetic variants of PPCM and any potential genotypic or phenotypic correlations.

All women included in the study were retrospectively recruited from international institutions using the Heart Failure Association of the European Society of Cardiology Working Group, which defines PPCM as the development of heart failure and a LVEF of 45% or less towards the end of pregnancy or in the months following delivery, where no other cause is identified.

In total, a cohort of 654 women who provided clinical information and DNA was identified by investigators. Of these, 469 met the criterion for satisfying clinical and sequencing data quality metrics. Using next-generation sequencing performed on 67 genes, investigators planned to identify and assess burden of truncating and missense variants. For the purpose of analysis, data obtained from the MyCode Community Health Initiative at Geisinger in Pennsylvania and New Jersey served as the reference population.

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Among the patients included in the study, 10.4% bore truncating variants in TTN (TTNtvs) compared to 1.2% of the referent population (OR, 9.4; 95% CI, 6.97-12.71; Bonferroni-corrected P=1.2x10-46). Additionally, investigators identified overrepresentation of truncating variants in FLNC (OR=24.8, 95% CI, 8.83-69.38; Bonferroni-corrected P=7.0x10-8), DSP (OR=14.9; 95% CI, 6.51-34.06; Bonferroni-corrected P=1.0x10-8), and BAG3 (OR=53.1; 95% CI, 6.19-454.96; Bonferroni-corrected P=0.02), which were not previously associated with PPCM.

Investigators noted the results of their genetic analysis suggested the profile of PPCM was highly similar to that found in patients with non-ischemic dilated cardiomyopathy.

When assessing clinical presentation based on presence of truncating variants, results indicated women with TTNtvs had lower LVEF than women without TTNtvs, but these groups did not differentiations significantly in timing of presentation following delivery, prevalence of preeclampsia, or rates of clinical recovery.

"We believe this study shows how important genetic screening and counseling are for women who develop PPCM, something that isn't currently common practice, and perhaps even for their female family members of child-bearing age," Arany said. "As a physician, knowing you have a patient with PPCM who shows these genetic mutations would lead you to make changes in care, such as lowering the threshold for defibrillator use in the case of high-risk variants, or counseling family members on their risk of developing PPCM."

This study, “Genetic and Phenotypic Landscape of Peripartum Cardiomyopathy,” was published in Circulation.