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OUR RESEARCH
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Treatment of atrial fibrillation using extracellular vesicles
Atrial fibrillation (AF) is a heart disorder that affects over 12 million people in the US. It costs the US healthcare system about $26 billion each year and leads to over 450,000 hospitalizations and more than 158,000 deaths. AF raises the risk of stroke, heart failure, and heart attacks. Currently, there is no cure for AF. The main treatments are medications and a procedure called ablation, but these only manage the symptoms and work for about half of the patients. Additionally, both treatments have risks. No new successful drugs for AF have been introduced in over 20 years, and the current treatments do not address the root causes of AF.
To meet this challenge, we have developed techniques to prevent atrial fibrillation that rely on a novel biologic, named extracellular vesicles. Extracellular vesicles are fluid filled microparticles created and released from the membrane of stem cells. They contain factors that participate in cell-to-cell signaling to influence tissue function.
Atrial fibrillation (AF) is a heart disorder that affects over 12 million people in the US. It costs the US healthcare system about $26 billion each year and leads to over 450,000 hospitalizations and more than 158,000 deaths. AF raises the risk of stroke, heart failure, and heart attacks. Currently, there is no cure for AF. The main treatments are medications and a procedure called ablation, but these only manage the symptoms and work for about half of the patients. Additionally, both treatments have risks. No new successful drugs for AF have been introduced in over 20 years, and the current treatments do not address the root causes of AF.
To meet this challenge, we have developed techniques to prevent atrial fibrillation that rely on a novel biologic, named extracellular vesicles. Extracellular vesicles are fluid filled microparticles created and released from the membrane of stem cells. They contain factors that participate in cell-to-cell signaling to influence tissue function.
Recently, we have provided the world's first proof that extracellular vesicles can prevent atrial fibrillation (doi.org/10.1172/jci.insight.163297). Our research shows that injecting extracellular vesicles into the atrial muscles can suppress inflammation and tissue damage, preventing atrial fibrillation in 90% of cases. This treatment results in smaller, more normal atria without the residual scarring typically caused by inflammation. Importantly, this effect occurs equally well in both males and females.
Although there is still much we do not know about this promising new therapeutic, we have found that extracellular vesicles can act like a drug. They have a dose-response relationship with atrial inflammation and scarring: the more extracellular vesicles delivered to the atria, the greater the therapeutic effect (doi.org/10.7150/thno.89520).
We also know that extracellular vesicles target at least two mechanisms:
1. Over the past 10 years, research has shown that many forms of atrial fibrillation are caused by the activation of the NLRP3 inflammasome. Extracellular vesicles contain nucleic acids and proteins that prevent this activation. When delivered to the atria, they target the inflammatory and structural cells in the tissue, preventing the activation of the NLRP3 inflammasome just like a drug (doi.org/10.7150/thno.89520).
2. Atrial fibrillation often results from increased scar burden in the atria. We have found that extracellular vesicles can directly inhibit the scar-forming cells of the atria, the fibroblasts, preventing them from proliferating and creating new scar tissue (doi.org/10.1172/jci.insight.163297).
Masson's trichrome stain showing the effect of extracellular vesicles on atrial tissue after open heart surgery.
Top: Atrial tissue without treatment with extracellular vesicles, displaying extensive scar tissue (blue).
Bottom: Atrial tissue treated with extracellular vesicles, showing significantly reduced scar tissue (blue) and more normal tissue structure (red).
Note: Red tissue represents normal, healthy tissue, while blue tissue indicates scar tissue.
Based on these exciting results, future work will focus on implementing these therapies for patients suffering from atrial fibrillation. These approaches have gained traction within the community of patients suffering from and at risk for atrial fibrillation. Recently, we showed that acceptance of EV therapy has improved, with a majority expressing willingness to participate in clinical trials and accept the therapy (doi.org/10.1016/j.cjco.2024.04.003).
Looking forward, EV therapy has the promise to enhance the management of atrial fibrillation beyond the current treatment paradigm, which is focused on palliating symptoms rather than addressing the fundamental drivers of the disease.
Looking forward, EV therapy has the promise to enhance the management of atrial fibrillation beyond the current treatment paradigm, which is focused on palliating symptoms rather than addressing the fundamental drivers of the disease.
Modeling of cardiac sarcoidosis for disease discovery and treatment
Sarcoidosis is a disease where small clusters of inflammatory cells called granulomas form in various parts of the body. The exact cause is unknown, but research suggests it might be an immune response to an unidentified trigger in people with a genetic predisposition. While it most commonly affects the lungs and lymph nodes, it can also impact the heart, liver, spleen, skin, eyes, and other organs, although less frequently.
Recently, there has been an increase in the diagnosis of cardiac sarcoidosis, where the heart is affected. A Finnish study reported a more than 20-fold increase in cardiac sarcoidosis diagnoses from 1988 to 2012.
The symptoms of cardiac sarcoidosis can vary depending on the location, severity, and activity of the disease. Common symptoms include irregular heart rhythms, ventricular arrhythmias, and heart failure. Corticosteroid therapy is often recommended for managing cardiac sarcoidosis, even though there is limited evidence supporting its effectiveness because, to date, there has been no model of cardiac sarcoidosis.
To address this knowledge gap, we explored the use of microparticles to create a reproducible animal model of cardiac sarcoidosis. We focused on carbon nanoparticles because sarcoidosis, characterized by inflammatory granulomas, often forms in response to a seemingly harmless foreign body like carbon nanoparticles. These by-products of combustion can cause a disease similar to sarcoidosis in the lungs. For example, firefighters exposed to carbon nanoparticles often have granulomas in their lungs weeks to months after exposure.
In our study, we applied this technology to the heart. We hypothesized that mice exposed to microparticles, which mimic the agents causing sarcoidosis, would show the primary pathological and histopathological characteristics of cardiac sarcoidosis. To test this idea, we investigated whether injecting carbon nanotubes into the heart tissue could reproduce the key features of cardiac sarcoidosis, specifically granuloma formation, irregular heart rhythms, and fibrosis.
Sarcoidosis is a disease where small clusters of inflammatory cells called granulomas form in various parts of the body. The exact cause is unknown, but research suggests it might be an immune response to an unidentified trigger in people with a genetic predisposition. While it most commonly affects the lungs and lymph nodes, it can also impact the heart, liver, spleen, skin, eyes, and other organs, although less frequently.
Recently, there has been an increase in the diagnosis of cardiac sarcoidosis, where the heart is affected. A Finnish study reported a more than 20-fold increase in cardiac sarcoidosis diagnoses from 1988 to 2012.
The symptoms of cardiac sarcoidosis can vary depending on the location, severity, and activity of the disease. Common symptoms include irregular heart rhythms, ventricular arrhythmias, and heart failure. Corticosteroid therapy is often recommended for managing cardiac sarcoidosis, even though there is limited evidence supporting its effectiveness because, to date, there has been no model of cardiac sarcoidosis.
To address this knowledge gap, we explored the use of microparticles to create a reproducible animal model of cardiac sarcoidosis. We focused on carbon nanoparticles because sarcoidosis, characterized by inflammatory granulomas, often forms in response to a seemingly harmless foreign body like carbon nanoparticles. These by-products of combustion can cause a disease similar to sarcoidosis in the lungs. For example, firefighters exposed to carbon nanoparticles often have granulomas in their lungs weeks to months after exposure.
In our study, we applied this technology to the heart. We hypothesized that mice exposed to microparticles, which mimic the agents causing sarcoidosis, would show the primary pathological and histopathological characteristics of cardiac sarcoidosis. To test this idea, we investigated whether injecting carbon nanotubes into the heart tissue could reproduce the key features of cardiac sarcoidosis, specifically granuloma formation, irregular heart rhythms, and fibrosis.
The images below show the results of injecting carbon nanotubes into the heart. The first image on the left shows a cross-section of the heart, with a small lesion highlighted in the top area. The middle image zooms in on this lesion, showing the surrounding heart muscle tissue. The lesion itself is characterized by the presence of dark clusters of cells, which are granulomas. The third image on the right provides an even closer view, revealing the detailed structure of these granulomas. These lesions closely resemble those found in cardiac sarcoidosis, showing how the injection of carbon nanotubes can mimic the disease in the heart.
Although the injection of carbon nanotubes produced characteristic sarcoid lesions and conduction block, it did not affect the scar burden or dimensions of the treated ventricles. We hypothesized that an additional stressor might be needed to produce the pro-fibrotic disease seen in cardiac sarcoidosis patients. Therefore, we investigated the impact of simultaneous transverse aortic constriction on the structural response to carbon nanotube injection.
We found that priming the innate immune system with transverse aortic constriction prior to intramyocardial injection of carbon nanotubes enhanced ventricular fibrosis and increased left ventricular mass in a manner similar to clinical cardiac sarcoidosis.
We found that priming the innate immune system with transverse aortic constriction prior to intramyocardial injection of carbon nanotubes enhanced ventricular fibrosis and increased left ventricular mass in a manner similar to clinical cardiac sarcoidosis.
The top image on the figure shows the results of carbon nanotube injection combined with transverse aortic constriction, displaying enhanced ventricular fibrosis.
The bottom image shows the results of carbon nanotube injection alone, which did not result in increased scar burden or changes in ventricular dimensions.
Our model, which reproduces the symptoms of cardiac sarcoidosis, is a step forward in early diagnosis and treatment. It enables the discovery of biomarkers for non-invasive detection and monitoring of the disease. Ideal biomarkers should be specific, sensitive, non-invasive, reliable, and affordable. Currently, no biomarkers for sarcoidosis are in clinical use.
This model also opens avenues for new treatments. We found that cardiac sarcoid lesions might be linked to nanoparticles from combustion by-products. Combining heart injections with lung inhalation could better mimic the chronic inflammation seen in patients.
This model also opens avenues for new treatments. We found that cardiac sarcoid lesions might be linked to nanoparticles from combustion by-products. Combining heart injections with lung inhalation could better mimic the chronic inflammation seen in patients.
