Researchers have created one of the first maps to reveal gene activity and connectivity as the heart shuts down

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Scientists investigating heart failure have been limited to studying diseased heart tissue in the lab – understandably, as people don’t tend to pluck out a healthy heart for the sake of research.

But now, scientists with access to unusable, yet still healthy, donor hearts have been able to investigate the genomic pillars behind the transition from healthy hearts to heart failure.

In doing so, researchers at the Stanford University School of Medicine and their collaborators have created one of the first maps to reveal gene activity and connectivity as the heart shuts down.

Euan Ashley, MB ChB, DPhil, professor of medicine, of genetics and of biomedical data science at Stanford, calls it a gene network.

These networks, he said, are akin to social networks. “Let’s say we traced the whereabouts of the human resources department at Stanford. We could see that they tend to park in the same area, go to the same office, and get lunch in the same place,” he said. “They move together, and so it can be reasonably inferred that they are somehow related to each other.”

Tracing a gene network for heart failure is like that, only instead of watching physical movements, Ashley and his collaborators watched for changes in gene expression, paying attention to how it changes as healthy hearts degenerates.

By delineating these gene networks, the group has discovered one gene in particular that seems to be at the center of the action.

It appears to be highly connected in heart failure, meaning its activity is similar to that of many neighbors. What’s even more exciting,

Ashley said, is that when the researchers disabled the function of this gene in mouse models of heart failure, the mice were protected and did not succumb to the cardiac condition.

“This study has a truly unique angle, which is that we had precious, healthy human tissue and we used it to tell us something new about how a disease manifests,” said Victoria Parikh, MD, clinical instructor of cardiovascular medicine.

“And now someday we might even be able to translate that into a treatment.”

A paper providing details of the study was published June 24 in Nature Communications. Ashley is the senior author. Parikh shares lead authorship with Pablo Cordero, Ph.D., a former Stanford graduate student.

Tracking the transition

Heart failure is not one simple condition, said Ashley, who treats cardiac patients at Stanford Health Care.

It’s more like an umbrella term that describes the heart’s inability to pump blood regardless of the cause.

“It could be a heart attack, a genetic cause, high blood pressure, a valve problem or something else entirely,” he said. “Regardless of how the heart deteriorates, we believe there’s one final, common pathway that ultimately leads to heart failure.”

Now, the web of genes that they’ve mapped is providing new insight into how that pathway unfolds, and which genes are crucial to its activation.

“Maybe someday we’ll be able to peer into a cell and watch as the networks are actively changing in real time,” he said.

“But right now what we have is human tissue that’s sort of frozen at a moment in time, and so we can use that to look at which genes are involved in this process.”

The group took tissue samples from more than 300 hearts (half from hearts removed from patients with heart failure who were getting heart transplants and half from healthy donor hearts) and ran genomic tests to determine gene expression activity.

It was essential, Ashley said, to have the healthy donor hearts available.

“Sometimes, for logistical reasons, a donor’s heart isn’t usable for transplantation, so instead of wasting these organs, we repurposed them for our study.”

Thanks to a dedicated, multi-institutional surgical team that worked around-the-clock – sometimes venturing out in the wee hours of night – the group secured more than 100 healthy hearts.

A new target

To date, studies that compare the genomics of healthy hearts and heart failure have taken place mainly in mice.

But with the healthy donor heart tissue, the team was able to compare and contrast genomic information in human hearts.

They found that fewer biological pathways were involved in heart failure compared with healthy hearts, but there were more genes involved in those pathways.

It’s almost as if the cells were “focusing” their efforts, presumably as part of a last-ditch effort to restabilize the declining heart, said Ashley.

Perhaps most telling, PPP1R3A had one of the biggest leaps in gene connectivity during the transition to heart failure, meaning it became associated with the activity of many other genes.

And although it hasn’t been implicated in heart failure in the past, its role does seem to fit with some of the symptoms, Ashley said.

The heart’s energy source typically comes from fatty acids, but it switches to glucose when it goes into failure. PPP1R3A as a central regulator makes sense because the gene plays a critical role in the metabolism of glucose within cells, Ashley said.

What’s more, the same networks that pointed researchers to PPP1R3A also turned up dozens of other new gene interactions during heart failure.

Ashley and colleagues confirmed PPP1R3A’s causal role in heart failure by testing the effect of the gene – or lack thereof – in mouse models of high blood pressure. It turned out that mice lacking the PPP1R3A gene maintained normal heart function, whereas those with the gene succumbed to heart failure.

“Across the population, there are plenty of people with high blood pressure who never go into heart failure, and there are some that do,” Ashley said. “We’re sort of mimicking that in these mouse studies. If we were able to inhibit this gene somehow in humans, we could potentially have a therapeutic drug that could protect patients from heart failure.”


Heart failure

Heart failure means that your heart is not pumping blood around your body as effectively as it should. 

Having heart failure doesn’t mean that your heart has stopped working, but that your heart needs some support to help it work better.

Heart failure a long-term condition that often gets worse over time. It can’t be cured, but with treatment and lifestyle changes, many people can have a good quality of life. It can occur at any age, but is most common in older people.

Symptoms of heart failure

The main symptoms are:

  • Shortness of breath when you are being active or at rest.
  • Swollen feet, ankles, stomach and around the lower back area.
  • Feeling unusually tired or weak.

Symptoms occur because your heart is not able to pump blood around the body efficiently. This can lead to a build-up of fluid that backs up into the lungs, which causes breathlessness. Also because the heart is not pumping properly it can cause fluid retention, leading to swelling in your legs, ankles, feet or in the small of your back or abdomen. 

You may also feel extremely tired because your heart is not able to deliver enough blood and oxygen to the muscles in your body.

You should see your GP if you begin to experience any of these symptoms.

To find out more about managing the symptoms of heart failure, visit our living with heart failure page.

What causes heart failure?

There are lots of reasons why you may develop heart failure. It can be sudden or it can happen slowly over months or even years.

The most common causes are:

  • A heart attack – this can cause long-term damage to your heart, which can affect how well the heart can pump.
  • High blood pressure – this can put extra strain on the heart, which over time can lead to heart failure.
  • Cardiomyopathy – a disease of the heart muscle. There are different types which can either be inherited or caused by other things, such as viral infections.

Heart failure can also be caused by:  

  • Damaged or diseased heart valves
  • An abnormal heart rhythm (arrhythmia)
  • Congenital heart conditions – heart problems that you’re born with
  • A viral infection affecting the heart muscle
  • Some cancer treatments such as chemotherapy 
  • Excessive alcohol consumption 
  • Anaemia – a lack of oxygen carrying haemoglobin or red blood cells in your blood
  • Thyroid gland disease.

Pulmonary hypertension

Heart failure can be caused by pulmonary hypertension (raised blood pressure in the blood vessels that supply your lungs). This condition can damage the right side of your heart, leading to heart failure. In some cases the pulmonary hypertension itself is caused by an existing heart condition. 

Find out more about pulmonary hypertension on NHS Choices and PHA UK.

Amyloidosis

Heart failure can also be caused by a rare group of conditions called amyloidosis. This is when abnormal proteins, called amyloid, build up in organs (such as the heart, kidneys and liver) and tissues, making it difficult for them to work properly. Without treatment, this can lead to organ failure.

If amyloidosis affects the heart it is called cardiac amyloidosis – or ‘stiff heart syndrome’. Cardiac amyloidosis tends to make the ventricles (the two lower pumping chambers of the heart) stiff, making it more difficult to pump blood around the body.

About 600 new cases are diagnosed in the UK every year.

Visit NHS Choices for more information.

How is heart failure diagnosed?

To diagnose heart failure, your doctor will ask you questions about your medical history, talk about your symptom(s) and do a physical examination.

This will include checking your heart rate and rhythm, taking your blood pressure, and checking if you have fluid in your lungs, legs and other parts of your body. 

In most cases you will also have further tests to confirm the diagnosis and guide how your symptoms are controlled.

You may hear your doctor talk about the ‘ejection fraction’ of your heart. This refers to the amount of blood that is pushed out of your left ventricle every time your heart beats. It’s usually expressed as a percentage – over 50% is considered normal. 

Some people with heart failure have a normal ejection fraction, so ejection fraction is used alongside other tests to help diagnose heart failure.

Treatments 

While there isn’t a cure for heart failure at the moment, the treatments available help to control symptoms leading many people to live full and active lives.

Your doctor is likely to prescribe drugs that will help to improve your symptoms, keep you as well as possible, help prevent your condition from getting worse and help to improve your life expectancy.

Some people with heart failure will benefit from a pacemaker or ICD, which help to improve the pumping action of your heart. Your doctor will talk to you about these treatments if they are the right option for you. 


More information: Pablo Cordero et al. Pathologic gene network rewiring implicates PPP1R3A as a central regulator in pressure overload heart failure, Nature Communications (2019). DOI: 10.1038/s41467-019-10591-5

Journal information: Nature Communications
Provided by Stanford University Medical Center

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