Unravelling the genetics of pregnancy and heart failure

 6 January 2016   Institute News

Scientists have found that women who suffer unexplained heart failure towards the end of pregnancy or shortly after giving birth share certain genetic changes.

The finding provides some explanation for this mysterious condition, and suggests that by testing relatives, other women who carry the same genes, and who might face similar risks, could be identified early. They could then be monitored closely and treated more swiftly if needed. In the future preventative treatment might be developed too.

Scientists uncover genetic links in heart disease and pregnancy

Scientists uncover genetic links in heart disease and pregnancy (Credit: Tatiana Vdb)

Normal pregnancy is a challenge for the cardiovascular system, with up to a 25 per cent increase in heart rate, and 50 per cent increase in the volume of blood pumped in a minute. In some previously healthy women the heart just can’t cope. Around the time of childbirth the heart enlarges, and stops pumping properly – classic symptoms of heart failure. This can lead to death or the need for a heart transplant, and at the moment doctors don’t know who this will happen to.

Around 1 in every 1000 women in Europe and the US suffers from this condition, known as peripartum cardiomyopathy (PPCM). Elsewhere there are geographic hotspots, including Nigeria and Haiti, where the number can be as high as 1 in 100.

Women who suffer from pre-eclampsia, those pregnant with twins and older pregnant women are all known to be at higher risk of developing PPCM. The cause is unknown, though theories about contributing factors include: an auto-immune response, undiagnosed heart damage, too much salt or too little selenium in the diet.

The teams found that the 170 or so women they tested carried a higher number of genetic changes than normal. The team decoded genes that can cause rare inherited forms of cardiomyopathy, and found that women with PPCM had a very similar genetic profile to patients with dilated cardiomyopathy (DCM) – a condition that runs in families.

Cardiologist James Ware, Clinical Senior Lecturer in Genomic Medicine at the MRC’s Clinical Sciences Centre (CSC), based at Imperial College, is lead author of the paper describing the results, which he described as encouraging news: “DCM is managed as an inherited condition: first degree relatives of affected individuals are offered genetic screening. Our results suggest that genetic diagnostics and family management may have similar value in PPCM.”

“PPCM has a mortality rate of 5 to 10 per cent, so being able to shed light on why it occurs in some women and not others is an important development and could ultimately save lives. Further research is needed to better understand the value of genetic information in determining the prognosis of PPCM.”

The study follows collaboration between researchers at a number of centres around the world including the Royal Brompton Hospital in London, Harvard Medical School and the Perelman School of Medicine at the University of Pennsylvania in the US, and is published today in The New England Journal of Medicine.

The researchers found that women with PPCM and patients with DCM shared abnormalities in a gene that codes for a protein called titin. Titin is the largest protein in the human body and acts like a spring within muscle tissue, including the heart. Titin’s size is crucial to its function, and some DCM is due to mutations that disrupt titin and make the protein shorter. This leads to hearts that are ‘baggy’ and stretched with thin muscle walls, that are too weak to pump blood around the body effectively, and which can cause sudden death in the 1 in 250 people affected.

The protein’s size is altered because the patients have a mutation in the titin gene. The team found this same sort of genetic change in one in ten of the women with PPCM that they studied – about the same as the proportion of patients with DCM that carry this titin-shortening variant.

“Until now, we had very little insight into the cause of peripartum cardiomyopathy,” said the study’s senior author Dr Zoltan Arany, an associate professor of Cardiovascular Medicine in the Perelman School of Medicine at the University of Pennsylvania. “There had been theories that it was linked to a viral infection, or paternal genes attacking the mother’s circulatory system, or just the stresses of pregnancy. However, this research shows that a mutation in the TTN (titin) gene is the cause of a significant number of peripartum cardiomyopathies, even in women without a family history of the disease.”

The researchers found that in women with this genetic variant their heart was pumping less well after a year. Testing for this change may therefore prove a useful way to predict likely outcome, enabling closer surveillance of those at higher risk.

Dr Arany added: “These findings will certainly inform future peripartum cardiomyopathy research, with possible implications on genetic testing and preventative care, though more research is unquestionably needed. We’re continuing to follow these women and we’re gathering data for hundreds of others around the world, with the goal of identifying the cause of peripartum cardiomyopathy in the remaining 85 percent of women with this condition, and ultimately using what we learn to improve the care of these women and their newborns.”

Case study

Penny Davis, 34, developed heart palpitations and shortness of breath while pregnant with her three-year-old daughter Poppy in 2011. By the time she was 18-weeks pregnant she was fainting and having blackouts, and a 22-week scan found her heart was beating too fast. Subsequent tests, including an electrocardiogram (ECG) and an echocardiogram, found a heart abnormality and she was later diagnosed with PPCM. Penny, a part-time HR manager from Walton-on-Thames in Surrey, said:

“Finding out there was something wrong with my heart while I was pregnant felt like the end of the world. Because I was pregnant the treatment was limited and this was very worrying. I was prescribed beta blockers and my palpitations calmed down.

“It was a huge relief when Poppy was born in January 2012 with no health problems. I had been told PPCM could get worse after birth and it did straightaway. A few days after the birth I thought I was dying because I had strong palpitations and felt so dizzy. I was prescribed ACE inhibitors and the term “heart failure” was used by the team at my local hospital for the first time – they had avoided saying it before so not to stress me out during pregnancy. It hit home how bad it was and that I may never get better.”

Penny was told she could not breastfeed due to her medication and was advised to reduce her fluid intake and adopt a low salt diet to aid her heart function. Doctors also told her it would not be safe for her to have more children.

“Having to accept I would only have one child was like going through a grieving process. I made the most of everything with Poppy, thinking I’d never be able to do it again.”

Penny was referred to experts at Royal Brompton Hospital, in June 2012, who suspected her PPCM was connected to a thyroid problem and that, if this was the case, she may be able to have more children.

“I had hope for the first time. The care at Royal Brompton was incredible – I had so many tests so the team could really understand my case. My heart totally recovered and I have come off ACE inhibitors, but I’m still monitored carefully.

“I was overjoyed to find out I was pregnant last year, and I’m due in April. I never thought it would be possible. My heart function dropped slightly during pregnancy but it has stabilised and I’m being scanned every four weeks. Every so often I panic a bit because of what happened last time, but I know I’m in good hands now.”

This latest study was led by Dr Zoltan Arany in the Perelman School of Medicine at the University of Pennsylvania together with professors Christine and Jon and Seidman at Harvard Medical School and Dr Dennis McNamara at the University of Pittsburgh Medical Center. Co-authors include Dr Stuart Cook, who leads the Cardiovascular Magnetic Resonance Imaging and Genetics group at the CSC; Dr Sanjay Prasad, a consultant cardiologist and honorary senior lecturer at Imperial College and Francesco Mazzarotto, a PhD student working with Dr Cook and Dr Ware at the National Heart and Lung Institute.

The study builds on a substantial programme of research around the role of titin in the heart by the teams from the CSC, Imperial College and Harvard.

Dr Ware did his PhD and a post-doc at the CSC, before being appointed as a Clinical Lecturer at Imperial College. He has recently spent a year in the Genetics Department at Harvard Medical School in Boston – where he carried out this work in the laboratory of Professors Jon and Christine Seidman. He returned to the CSC from Boston in April to start a new group at Imperial College, working closely with Dr Cook. Dr Ware is funded by a Fellowship from the Wellcome Trust and is honorary consultant cardiologist at Royal Brompton hospital.

The patients with dilated cardiomyopathy were recruited by the NIHR Cardiovascular Biomedical Research Unit at Royal Brompton and Harefield NHS Foundation Trust and Imperial College London.


Read previous publications here and here. And earlier press coverage by genomeweb, Imperial College London and Reuters.

For further information contact:

Susan Watts
Head of Communications and Public Engagement
07590 250 652
0208 383 8247