Study Finds Common Genetic Mutations in Dilated and Peripartum Cardiomyopathies

By Eileen Hsich, MD

A major multicenter study, recently published in the New England Journal of Medicine, has advanced understanding of what causes peripartum cardiomyopathy and its relation to dilated cardiomyopathy. Cleveland Clinic participated in the study, and this article briefly reviews what prompted the study and its implications for practice and further research.

Long-standing questions around peripartum cardiomyopathy

For years, there has been limited understanding of why heart failure develops in a subgroup of women late in pregnancy or during the early postpartum period. Some studies have suggested that peripartum cardiomyopathy is triggered by hormones. While the condition is uncommon (affecting 1 in 4,000 U.S.) and usually resolves, it can persist with severe consequences. Serious associated adverse events include death (which occurs in about 5 percent of patients) and end-stage heart failure requiring mechanical circulatory support or heart transplantation (in another 5 percent of patients).

Women with peripartum cardiomyopathy are often referred to a specialized program such as Cleveland Clinic’s Women’s Heart Failure Clinic. Our patients exhibit common risk factors for peripartum cardiomyopathy such as gestational hypertension, pre-eclampsia, multiple births and older age. We also have noticed that some patients without any identifiable cause at the time of diagnosis are later found to have familial cardiomyopathy, raising the possibility that peripartum cardiomyopathy may represent more than one entity.

Sorting out the shared features with dilated cardiomyopathy

It has long been acknowledged that peripartum cardiomyopathy and idiopathic dilated cardiomyopathy share clinical features such as decreased systolic function, an enlarged heart and nonspecific histologic findings on biopsy. But they have been considered separate diseases.

Cleveland Clinic has recently participated in two studies investigating these conditions:

• Intervention in Myocarditis and Acute Cardiomyopathy 2 (IMAC-2), which followed patients, including a subgroup with peripartum cardiomyopathy, for four years to assess the effects of medical therapy
• Investigations in Pregnancy Associated Cardiomyopathy (IPAC), which looked at the natural history of the disease and enrolled a large number of Cleveland Clinic patients

Research has found mutations in a number of genes to be a cause of dilated cardiomyopathy. Given dilated cardiomyopathy’s similarities with peripartum cardiomyopathy, it was important to determine whether genetics was also a factor in the latter. So Cleveland Clinic joined the above-mentioned multicenter study, which included IPAC researchers, to investigate the genetics of peripartum cardiomyopathy.

The study in brief

The investigation included 172 women with peripartum cardiomyopathy, including participants in the IMAC-2 and IPAC studies. Genetic sequencing was performed on 43 genes associated with dilated cardiomyopathy. The results were then compared with those from a cohort of 332 patients with dilated cardiomyopathy and also from a reference population of more than 60,000 people.

Our findings included the following:

• 15 percent (n = 26) of study participants had mutations in the 43 genes of interest, which was similar to the rate in the cohort with dilated cardiomyopathy and significantly higher than the 4.7 percent of participants in the reference population
• 26 genetic variants were found in eight genes
• Most of the variants (65 percent) occurred in the TTN gene, which was also true of the cohort with dilated cardiomyopathy

Genetic variants occurred equally among participants with and without a family history of cardiomyopathy. The prevalence of variants was ten times higher in women without hypertension. In IPAC, these patients were also less likely to recover myocardial function over time.

Screening and management implications abound

For years, the medical community has disagreed over whether peripartum and dilated cardiomyopathy are essentially the same or different diseases. This study is the first to offer evidence that the two diseases share genetic variants. It is also the first study to provide a genetic etiology for those patients who fail to recover myocardial function.

These findings have a number of significant implications for screening, treatment and counseling:

• The gene-based diagnosis that is currently available for familial dilated cardiomyopathy could now be beneficial for a subgroup of peripartum cardiomyopathy patients as well.
• In light of our finding that women with genetic variants have worse outcomes, we now have a potential prognostic indicator for peripartum cardiomyopathy.
• Genetic testing could help all patients make a more informed decision on whether to consider a second pregnancy, remain on medications for life and pursue aggressive medical care.
• For the offspring of patients with peripartum cardiomyopathy, genetic testing could help guide their medical care and prospective pregnancies.

Next steps

Further study is needed to explore the value of changing medical therapy based on genetic mutations and to examine the possibility of safe subsequent pregnancies in patients whose peripartum cardiomyopathy does not have a genetic cause. Follow-up studies will be conducted to further advance the field.

Dr. Hsich is Director of the Women’s Heart Failure Clinic and Associate Medical Director for the Heart Transplant Program at Cleveland Clinic.