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It Takes A Village To Treat Heart Valve Disease: Integrating Basic Discovery Science With the Development of New Therapeutics

February 13, 2018
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As a newly appointed assistant professor sitting at a career development workshop I hear, “You need to be at the forefront of bench-to-bedside research to make a real difference!”

In my mind, I am thinking, “I think I’ll just play it safe and stick to ‘the bench’. I’m a molecular biologist – it’s what I know. I’ll leave ‘building scientific bridges’ to the more established gurus in the field.”


My research career has been focused on understanding the molecular cues that promote the onset and progression of heart valve disease in pediatric and adult patients. Without hesitation, I can reiterate the opening two lines of my grant submissions: “There are no effective treatments to treat heart valve disease other than surgical repair and replacement, and over 90,000 surgeries are performed in the United States each year, costing in excess of $2 billion.”

Although I write it frequently, what does this really mean?

It means that if your valves fail, as they do for 5 million Americans, your condition cannot be treated by medication. Ultimately, you will be referred to a cardiothoracic surgeon. Even worse, if you receive no effective treatment, there is an associated risk of up to 80 percent that you will progress to heart failure or death.

Previous pharmacological initiatives focused on targeting risk factors of valve disease in affected individuals, particularly elevated lipoprotein levels. The outcomes of administering oral statin therapy to lower low-density lipoproteins (LDL) have been mixed. Despite some studies initially reporting benefits, others have shown conflicting results, with some stating no beneficial effect on valve function despite a significant drop in LDL-cholesterol levels. Therefore, statin therapy for valve disease remains unsubstantiated, and the field continues to explore better alternatives. However, to date, none have been found. This is likely due to the complex, multi-factorial nature of valve disease and the difficulty in targeting many diverse contributors.

This deficiency in treatment options is not a new phenomenon. In 2006, when my independent career began, my grant applications still started with highlighting the need for alternative therapies. However, I stayed focused building my lab and asking more fundamentally basic, but important, questions such as “What are heart valves made of?” and “What signaling pathways are critical for normal valve formation?”

For many years this approach worked well for me. This strategy led to novel basic science discoveries showing for the first time that healthy heart valves are composed of three highly organized layers of extracellular matrix and two major cell types: valve endothelial cells and valve interstitial cells. My lab went on to show that abnormal changes in organization and composition of the valve matrix are characteristic of disease and contribute to structural failure – together demonstrating that maintaining extracellular matrix homeostasis is critical for preserving healthy valve function.

Over the past decade, the field has collectively grown to understand that homeostasis of the valve matrix is regulated by valve interstitial cells (known as the ‘doing cells’ in my lab), while in turn, their function is regulated by overlying valve endothelial cells (or ‘dictator cells’). Studies by several trainees through my lab over the years have identified several key molecular signals that govern valve cell-cell and cell-matrix communications in healthy valves and reported how these are altered in disease. While descriptive and somewhat “safe,” these molecular studies have identified potential signaling pathways that could be therapeutically targeted to correct valve cell function in disease states and subsequently improve matrix homeostasis and overall valve function.

Now, as an associate professor at Nationwide Children’s, I don’t feel the need to keep “playing it safe” at the bench. I am thinking more broadly and wondering: “How can we improve clinical outcomes of heart valve disease sufferers through the discovery of alternative, mechanistic-based therapies?”

I started by sending a few emails, which led to drinking coffee with other investigators, and I soon began to sense mutual excitement and motivation from my colleagues to “build.” Build? I haven’t really been a scientific builder, or a builder of any kind really, other than constructing a Star Wars Fighter Jet from Lego for my younger brother (now 33) in 1994. However, the prospect of building a heart valve research interest group didn’t faze me as much as the instruction book for The Millennium Falcon.

In response to my new question, I also changed my approach. First things first, I added the word “we” to my question, and second, I planned a Heart Valve Research Group meeting to begin piecing together the complex puzzle of multifaceted heart valve disease. While the task may be just as complex as my brother’s Lego kit, I have the advantage this time of being part of a dynamic, motivated team of outstanding experts in multidisciplinary areas of heart valve research.

I am still a molecular biologist, but at Nationwide Children’s, I am surrounded by a plethora of researchers with related and diverse interests in heart valves. Down the hallway is a pediatric cardiologist and expert in aortic valve disease genetics. Across the hallway are leaders in the field of heart valve tissue engineering. In the operating room, we have two talented cardiothoracic surgeons that perform corrective valve surgeries in children weekly and strive to develop alternatives to overcome the current limitations of valve implants. In other hospital disciplines, we have radiologists advancing valve diagnostics through imaging, and reconstructing human valves by 3D printing. To top this off, bioengineers nearby at The Ohio State University are defining the contribution of biomechanics to heart valve disease.

With this expert team defined and connected, the goal is to transform the current autonomous ways of thinking and utilize multidisciplinary teams to integrate the multifaceted contributors of valve disease to discover novel and more effective mechanistic-based therapies. To date, the Heart Valve Research Interest Group at Nationwide Children’s and Ohio State has developed a strategic plan to promote frequent interaction between these diverse groups and cross-training of mentees. This plan has already increased the number of multiple principal investigator grant applications and publications, in addition to creating unique opportunities for trainees to combine differential skill sets. As the group builds in central Ohio and recognition grows outside our institutions, we welcome integration of our program across the country and beyond.

 

Image credit: Nationwide Children’s