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Topics: Five Questions, Pilot Funding

From Pilot Grant to Paradigm Change in Heart Valve Treatment

Five Questions with Elena Aikawa on rethinking calcification.

Elena Aikawa, MD, PhD, is on a mission to shift the paradigm in the treatment of calcific aortic valve disease, or calcific aortic stenosis. She dreams of a day when patients will be treated early, with a pill, to prevent the calcification that leads to this serious complication that can currently be treated only through heart intervention.

Her quest began nearly a decade ago when she received a pilot award through our 2014 advanced microscopy funding to use high-resolution imaging to investigate how calcification forms in valve disease. That project led to a second grant, then a third, catalyzing an ambitious translational research program that is seeking to turn basic-science discoveries into pharmacological treatments for a disorder that affects 40.5 million people worldwide and is on the rise as the global population ages.

Aikawa is professor of medicine and Naoki Miwa Distinguished Chair in Cardiovascular Medicine at Mass General Brigham.

What’s the clinical problem your lab is trying to solve?

My lab focuses on pharmacologic target discovery to treat calcification in arteries and valves, particularly valves. For me, it’s very, very important because there is no treatment whatsoever for valve disease outside of open-heart surgery, in which you open the chest, expose the heart, remove the valve, and replace it.

A less invasive procedure, trans-catheter valve replacement, is available only for very old or sick patients who might not withstand open-heart surgery, and it’s only available in the U.S. and some big European cardiac centers, leaving many patients around the world without access. That’s why we work so hard.

The conventional wisdom in cardiovascular medicine is that calcification isn’t necessarily a bad thing, but your results suggest otherwise. Does this work shift the paradigm?

People have argued that calcification is not a bad thing, that it stabilizes the atherosclerotic plaque and makes it less likely to rupture. I’m not sure that is a correct assessment. Even if one portion of your arterial tree is stabilized, another portion may develop these so-called microcalcifications. It’s a continuous dynamic process. You can have a combination of microcalcification and large calcification in dangerous places. The older or sicker you become the more problems you may have.

Others think calcification is part of the healing process. This is based on findings in infectious diseases like tuberculosis where the calcified capsule kind of isolates inflammatory processes. I don’t think calcification is normal healing. I think it’s healing gone wrong.

“I don’t think calcification is normal healing. I think it’s healing gone wrong.”

If you look at all these problems with calcification–plaque eruption, valve replacement, open-heart surgery–this is really a process that we need to treat early. I want pathologists, cardiologists, radiologists, and other medical specialists to understand that calcification is not innocent by any standard. It’s actually a pathological process that is pro-inflammatory. It’s very dangerous and harmful, and it needs to be treated as seriously as high cholesterol and other problems.

You are one of only two investigators who have received three Harvard Catalyst grants in a row. Walk me through the discoveries these grants sparked.

From the beginning, our project was very translational, but also quite basic. To understand how calcification develops, we needed to look at the very first step in the formation of these microcalcifications through calcified extracellular vesicles. In the valve, calcification is an enormous problem because the valve becomes stiff like a rock and no longer flexes appropriately. At that point the patient has a high risk of heart failure, so the valve has to be replaced.

Harmful microcalcifications are beyond the resolution of current imaging modalities. You cannot see them without the kind of high-resolution imaging available at the Harvard Center for Biological Imaging (HCBI) and the Center for Nanoscale Systems (CNS). Access to these imaging modalities was really driving our grant.

In that first grant, we developed a three-dimensional (3D) collagen/hydrogel model of valve calcification, because there was no adequate model yet. We incorporated the extracellular vesicles into collagen hydrogels and looked at their growth at different time points. Using the ELYRA super-resolution confocal microscopy and our 3D collagen model, we observed for the first time how individual extracellular vesicles start to form into microcalcifications. Eventually they merge with one another and become large macrocalcifications, just as we had hypothesized.

So now we had this great model, but it was very tedious to use. You needed to manually recreate it each time. The second grant enabled us to replicate the model using 3D bioprinting. A new bioprinter in the lab allowed us to print those collagen structures in small wells, which we then seeded with calcifying valvular cells or vesicles. We could then apply various target molecules to see how they might resolve or inhibit microcalcification.

That brought us to the next level and the third round of Harvard Catalyst funding, which enabled us to expand our bioprinting platform from a single well to 96 wells. Now we are able to do high throughput screening, which takes us from target discovery into drug development. We’re bringing it closer to the clinic.

The goal now is to develop a drug which can inhibit those molecules, which is not very easy. For that, we are collaborating with Kowa, a pharmaceutical company from Japan. The next step would be clinical trials, and hopefully some of them will be based on our original discoveries.

You’ve been an advocate for early treatment of cardiovascular disease and valve disease. How does this research fit into that advocacy?

Treating calcification after the fact is probably impossible, at least at the point where science stands now. I think we really need to start early.

“The dream to me is if patients could just take a pill that would prevent calcification or fibrosis and the valve would stay healthy, like taking a statin to treat atherosclerotic plaque progression.”

The problem is how do we identify this population of patients with early microcalcification? There is currently no imaging modality that can detect them. That is a big problem. I’m advocating and hoping that an imaging company will develop a method to visualize calcification at a very early stage.

One target population is those who are born with bicuspid valve disease – about two percent of the population. They develop calcification early on and typically need valve replacement in their 40s or 50s. Because we can identify them at birth, we could monitor their disease progression and at some point, start treating them to prevent open-heart surgery.

But you have to start early, before these vesicles coalesce to become micro- and macrocalcifications and damage the valve. That’s why it’s so important to understand their formation; it provides several target pathways that could be inhibited.

How might this eventually change clinical practice for valve disease?

I’m a dreamer. The dream to me is if patients could just take a pill that would prevent calcification or fibrosis and the valve would stay healthy, like taking a statin to treat atherosclerotic plaque progression. I hope we can do similar things to prevent calcification formation in the valve.

Imagine you take a pill, and you don’t need to have invasive valve replacement anymore. That’s a goal. I don’t know if I have enough time to achieve my goal, but this is something we are really hoping for one day.

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