Two proteins linked to heart failure in pregnant women

When pregnant women develop heart failure, two immune proteins may play a crucial role, a new study shows. The findings provide a mechanistic explanation of the condition and point to potential treatment targets, the researchers say.

It is extremely rare, but pregnant women do sometimes develop heart failure. For some, it becomes so severe that a heart transplant becomes necessary.

But what causes an otherwise healthy heart to fail during pregnancy? Researchers have now identified key molecular changes in the heart. The study shows that levels of two immune proteins are elevated in affected women and likely play a crucial role, suggesting that the disease arises from interaction between the heart and the immune system.

The discovery could help identify women at high risk of heart failure during pregnancy and, in the longer term, open the door to new treatments, the researchers say.

“With this study, we gain better understanding of the mechanisms behind heart failure among pregnant women and how this type of heart failure differs from other forms. The hope is that, in the long term, we can find out how and which pregnant women develop heart failure and that drugs targeted at the underlying mechanisms can be developed,” says Alicia Lundby, Professor at the Department of Biomedical Sciences of the University of Copenhagen.

The research has been published in Molecular & Cellular Proteomics.

A closer look at heart proteins

Heart failure among pregnant women – peripartum cardiomyopathy (PPCM) – is fortunately so rare that most people have never heard of it.

For the very few who are affected during or immediately after pregnancy, however, it can have fatal consequences.

There is still limited knowledge about this condition—why natural changes in the heart during pregnancy in some cases develop into heart failure, and how PPCM differs from other types.

Alicia Lundby and her colleagues are working to develop and apply tools to better understand what happens in the heart during disease. The aim is to identify the molecular changes that drive heart disease and, in turn, relevant drug targets for further clinical research.

The researchers set out to investigate what changes in the heart when PPCM develops.

“We want to understand what drives the disease at the molecular level, so that in the long term we can contribute to creating more targeted treatments and diagnostics,” explains Alicia Lundby.

Studying protein content in heart tissue

To find answers, the researchers examined the protein content of heart samples from women with PPCM, women with other forms of heart failure and healthy women.

Since sampling from the heart is challenging, the material came from women who had undergone a heart transplant or from healthy women who had died.

The researchers used advanced omics techniques, which they have helped develop, to investigate changes in heart tissue.

These techniques make it possible to identify the proteins present in the tissue and quantify their relative abundance.

"With our techniques, we could look for differences between the three groups of women to see whether protein-level differences distinguish women who develop heart failure during pregnancy,” says Alicia Lundby.

Two proteins appear to link pregnancy to heart failure

At first, the picture resembled what was already known: a significant overlap with other forms of heart failure. But then a more distinct pattern began to emerge: women with PPCM had about 50 proteins altered, either elevated or reduced.

Within this pattern, two proteins stand out. These are the proteins chymase and carboxypeptidase A3.

Both proteins are involved in the activation of the immune system’s so-called mast cells.

In further analysis, the researchers examined blood from women with PPCM, other heart failures, and healthy pregnant women, and found elevated levels of chymase in the blood of women with PPCM, indicating that the signal is not confined to the heart and not driven by pregnancy alone.

And the pattern held: the findings were confirmed in an independent dataset, in which researchers had examined how genes are translated into proteins in the hearts of women with PPCM – reinforcing the hypothesis that immune activity may help drive the disease.

“Our findings are clinically relevant because they point to a specific drug target and could help to identify women at high risk of PPCM,” explains Alicia Lundby.

Existing drugs might already be useful

Alicia Lundby explains that the researchers now plan to build on their findings and validate them using additional data.

The challenge with a rare disease is that results are difficult to confirm in patient groups large enough to establish clear causal relationships.

The researchers also want to better understand why elevated levels of these proteins are linked to the development of heart failure.

So far, they have shown that chymase and carboxypeptidase A3 affect heart muscle cells – possibly by altering signalling and tissue structure – but exactly how remains unclear.

Drugs that target mast cells and their protein secretion already exist – precisely the mechanism highlighted in the study – and could dampen the signalling molecules and enzymes that affect the heart. However, these have not yet been investigated in PPCM.

“Our aim is to collaborate with networks of clinicians who treat women with PPCM and, through these networks, initiate a larger study into the link between PPCM and mast cell proteins. If we can confirm this link, it will be both interesting and relevant to investigate whether these drugs might have clinical potential in treating women with PPCM,” says Alicia Lundby.

She emphasizes that her work focuses on developing techniques for protein analysis, and that there is still a significant gap between laboratory research and clinical trials in humans.

“We are developing and applying new technologies to understand the fundamental mechanisms of the heart. Our techniques have taken a decade to refine but now provide robust measurements and unique insight at the molecular level. In the long term, this could pave the way for better diagnostics and more targeted treatment.,” concludes Alicia Lundby.