Cardiomyopathy at the Intersection of Bench and Bedside

Shira Berman; Huei-sheng Vincent Chen, MD, PhD; Daniel P. Judge, MD


March 05, 2013

Editorial Collaboration

Medscape &

In This Article

Editor's Note:
Arrhythmogenic right ventricular dysplasia (ARVD) cardiomyopathy is an uncommon inherited disorder that predisposes affected young individuals and athletes to ventricular tachycardia and sudden death.[1] Its late presentation has made it difficult for researchers to understand how the disease progresses over time, but such research is critical to the development of treatment strategies that can minimize disease-related morbidity and mortality.

In a unique collaboration between research scientists and clinicians, investigators at Sanford-Burnham Medical Research Institute and Johns Hopkins University's Center for Inherited Heart Disease harvested skin cells from adults with ARVD, reprogrammed the skin cells into stem cells, and then stimulated the stem cells to grow into cardiac muscle cells with adult-like energy production.[2] With this metabolic maturation-based "disease-in-a-dish" model of ARVD, researchers are now able to study how cardiac cells in patients with ARVD develop -- and better understand where they might intervene to prevent disease sequelae.

In an interview with Medscape, Huei-sheng Vincent Chen, MD, PhD, Associate Professor at Sanford-Burnham, and Daniel P. Judge, MD, Associate Professor and Medical Director of the Center for Inherited Heart Disease at Johns Hopkins University, discussed how this collaborative effort will help move the field forward.

A Disease-in-a-Dish Model for ARVD

Medscape: What do we already know about the pathogenesis and natural history of ARVD? What prompted you to look at new approaches for studying the development and progression of this disease?

Dr. Judge: ARVD is an inherited form of cardiomyopathy. Its name -- arrhythmogenic right ventricular dysplasia cardiomyopathy -- is actually descriptive of the disease process. In contrast with other forms of cardiomyopathy, in ARVD, fibrofatty scars develop, which creates a setup for arrhythmia. Research from my laboratory and others around the world identified specific genetic mutations that lead to defects in desmosomes, which play a role in cell-to-cell adhesion and stability of the cardiac muscle.[3] In people with this condition, these abnormalities can lead to life-threatening arrhythmias and sudden cardiac death. You tend to see it in athletes, but we're not exactly sure why, and it's not always the case.

Dr. Chen: Right now, the best we can do is to implant a defibrillator under the skin to shock patients into a normal rhythm so they won't suddenly die from an arrhythmia. We can prevent some deaths this way, but it doesn't change the disease course. Our goal is to establish a human disease model to discover what's really going wrong in their hearts so we can find a way to slow down the disease progression.

Medscape: Your approach was to create a "disease-in-a-dish" model using stem cells derived from skin cells of patients with ARVD. What are the benefits to this approach? Why did you think that this type of in vitro model would be suited to the study of this particular disease?

Dr. Chen: The model is based on technology developed by Dr. Shinya Yamanaka and for which he received a Nobel Prize in 2012. He took adult skin cells and converted them into embryonic-like stem cells that can grow into any type of tissue. We thought that if we could take skin cells from patients with ARVD and convert those cells into stem cells, we could then generate heart cells that have the specific genetic mutations that cause ARVD.

However, patients with ARVD don't present with early-stage disease, so we could not see how the disease develops over time. Now that we have figured out a way to establish this disease-in-a-dish model, we can track the pathology from the earliest stages to the latest stages of disease. We can look at how these heart cells are different from normal heart cells, why they go wrong, and when they go wrong. If we can identify the specific mechanisms that cause the dysfunction, we can look for drugs or some other way to prevent disease progression or to reverse it in some way.

More importantly, we can do this by just generating more cells any time we need them without repeatedly performing biopsies of patients' hearts to get more tissue for study.

Dr. Judge: Another thing to keep in mind is that, in studying a genetic disorder, we often use mouse models because it's easy to manipulate their DNA. But with this approach, we can study the entire human genetic background and human heart muscle cells, so we get a more complete picture of the disease pathology.

Dr. Chen: I agree. With the disease-in-a-dish model, we have to be able to capture most pathologies that normally happen in the patient's heart or the model is useless. This can be very difficult for diseases like ARVD because clinical signs and symptoms don't appear for 20 years or more; or even more so for Alzheimer disease, where it can take 5 or 6 decades for the disease to develop.

When we started this project, we put the cells in culture, grew them for a few months, and saw that they had junction protein abnormalities, which is consistent with what we know about patients with ARVD.[4] But the cells didn't die and didn't act abnormally, so we couldn't yet call it a disease model.

So we started thinking about human heart cell development. There's a fundamental difference between how fetal cells and adult cells use energy -- fetal cells mainly use glucose as their energy source, but adult cells prefer fat as their energy source.[5] It took us almost a year to get a working protocol, but we were finally able to convert these stem cells from very young, sugar-dependent, energy production stages to adult-like cells using fat as their main energy source.

This gave us mature cells, but they were still behaving normally. So we went through many clinical and laboratory studies and found a report that described abnormal expression of metabolic genes in the hearts of patients with ARVD.[6] When we activated these abnormal genes within the adult energy environment, we finally were able to replicate the disease in culture.

This 2-step process -- first inducing cell maturation and then activating abnormal genes -- makes sense not only to the people doing research but also to the clinicians who see patients manifesting symptoms in their late teens and early 20s. So this 2-step process makes this unique system a better, more clinically relevant model for ARVD.

Dr. Judge: I hope this will be the model of bench to bedside and back again from bedside to bench. We're excited about the potential for modulating these pathways that help energy use within the heart to see if the same things that we saw in the cells are associated with progression of disease. If you look at a family with ARVD, one person may have the genetic mutation and abnormal heart function, but a sibling or parent or child may have the same mutation and show no signs of disease. With research like this, we will be able to modulate the energy source and the metabolic changes and see how it might affect the association of disease with the mutation.