New research digs into the genetic drivers of heart failure, with an eye to precision treatments – STAT

When coronary arteries are blocked, starving the heart of blood, there are good medications and treatments to deploy, from statins to stents. Not so for heart failure, the leading factor involved in heart disease, the top cause of death worldwide.

Its whats on death certificates, said cardiologist Christine Seidman.

Seidman has long been interested in heart muscle disorders and their genetic drivers. She studies heart failure and other conditions that affect the myocardium the muscular tissue of the heart not the blood vessels where atherosclerosis and heart attacks come from, although their consequences are also felt in the myocardium, including heart failure.

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With her colleagues at Brigham and Womens Hospital and Harvard Medical School, she and a long list of international collaborators have been exploring the genetic underpinnings of heart failure. Based on experiments deploying a new technique called single-nucleus RNA sequencing on samples from heart patients, on Thursday they reported in Science their discovery of how genotypes change the way the heart functions.

Their work raises the possibility that some of the molecular pathways that lead to heart failure could be precisely targeted, in contrast to treating heart failure as a disease with only one final outcome.

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Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting, she said. To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

Seidman talked with STAT about the research, including how snRNAseq solves the smoothie problem, and what it might mean for patients. The conversation has been edited for clarity and brevity.

What happens in heart failure?

The heart becomes misshapen in one of two ways. It either becomes hypertrophied, where the walls of heart muscle become thickened and the volume within the heart is diminished, in what we call hypertrophic cardiomyopathy. Or it becomes dilated, when the volume in the heart is expanded and the walls become stretched. I think of it as an overinflated balloon, and that is called dilated cardiomyopathy.

Hypertrophy and dilatation are known to cause the heart over time to have profoundly diminished functional capacity. And clinically, we call that heart failure, much more commonly arising from dilated cardiomyopathy.

What does it feel like to patients?

When we see patients clinically, theyre short of breath, they have fluid retention. When we look at their hearts, we see that the pump function is diminished. That has led to a hypothesis of heart failure as sort of the end stage of many different disorders, but eventually the heart walks down a final common pathway. Then you need a transplant or a left ventricular assist device, or youre going to die prematurely.

What can be done?

Heart failure is a truly devastating condition, and it can arise early in life, in middle age, and in older people. There is no treatment for it, no cure for it, except cardiac transplantation, of course, which provides a whole host of other problems.

How did you approach this problem?

One of the questions we wanted to answer is, are there signals that we can discern that say there are different pathways and there are molecules that are functioning in those pathways that ultimately converge for failure, but through different strategies of your heart?

We treat every patient with heart failure with diuretics. We give them a series of different medications to reduce the pressure against which the heart has to contract. Im clinically a cardiologist, but molecularly Im a geneticist, so it doesnt make sense. If your house is falling down because the bricks are sticking together or if its falling down because the roof leaks and the water is pooling, you do things differently.

Tell me how you used single-cell RNA sequencing to learn more.

Looking at RNA molecules gives us a snapshot of how much a gene is active or inactive at a particular time point. Until recently, we couldnt do that in the heart because the approach had been to take heart tissue, grind it all up, and look at the RNAs that are up or down. But that gives you what we call a smoothie: Its all the different component cells those strawberries, blueberries, bananas mixed together.

But theres a technology now called single-cell RNA sequencing. And that says, what are the RNAs that are up or down in the cardiomyocytes as compared to the smooth muscle cells, as compared to the fibroblasts, all of which are in the cells? You get a much more precise look at whats changing in a different cell type. And thats the approach that we use, because cardiomyocytes [the cells in the heart that make it contract] are very large. Theyre at least three times bigger than other cells. We cant capture the single cell it literally does not fit through the microfluidic device. And so we sequenced the nuclei, which is where the RNA emanates from.

What did you find?

There were some similarities, but what was remarkable was the degree of differences that we saw in cardiomyocytes, in endothelial cells, in fibroblasts. Theres a signature thats telling us I walked down this pathway as compared to a different one that caused the heart to fail, but through activation or lack of activation of different signals along the way.

And that to me is the excitement, because if we can say that, we can then go back and say, OK, what happens if we were to have tweaked the pathway in this genotype and a different pathway in a different genotype? Thats really what precision therapy could be about, and thats where we aim to get to.

Whats the next step?

It may be that several genotypes will have more similarities as compared to other genotypes. But understanding that, I think, will allow us to test in experimental models, largely in mice, but increasingly in cellular models of disease, in iPS [induced pluripotent stem] cells that we can now begin to use molecular technologies to silence a pathway and see what that does to the cardiomyocytes, or silence the fibroblast molecule and see what that does in that particular genotype.

To my mind, thats the way to drive precision therapeutics. We know the cause of heart failure. We intervene in a pathway that we know is activated. And for the first time, we have that information now from human samples, not from an experimental model.

What might this mean for patients?

If we knew that an intervention would make a difference thats where the experiments are we would intervene when we saw manifestations of disease. So the reason I can tell you with confidence that certain genes cause dilated cardiomyopathy is theres a long time between the onset of that expansion of the ventricle until you develop heart failure. So theres years for us to be able to stop it in its tracks or potentially revert the pathology, if we can do that.

What else can you say?

I would be foolish not to mention the genetic cause of dilated cardiomyopathy. Ultimately, if you know the genetic cause of dilated cardiomyopathy, this is where gene therapy may be the ultimate cure. Were not there yet, but we certainly have the capacity to make small molecules to interfere with pathways that we think are deleterious to the heart in this setting.

My colleagues have estimated that approximately 1 in 250 to 1 in 500 people may have an important genetic driver of heart muscle disease, cardiomyopathy. Thats a huge number, but not all of them will progress to heart failure, thank goodness. Around the world, there are 23 million people with heart failure. Its what ends up on most peoples death certificate. It is the most common cause of death.

Its a huge, huge burden. And there really is no cure for it except transplantation. We dont have a reparative capacity, so were going to have to know a cause and be able to intervene precisely for that cause.

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New research digs into the genetic drivers of heart failure, with an eye to precision treatments - STAT