Study Shows ActRII Signaling Contributes to Heart Failure and Aging

As patient populations continue to live longer with heart disease, researchers at Massachusetts General Hospital are working to better understand the process of aging contributes to heart disease. Jason Roh, MD, MHS, cardiologist in the Corrigan Minehan Heart Center at Mass General, says, "age represents a dominant risk factor for most types of heart disease. We believe that if we better understand how the biological process of aging contributes to heart disease, this could lead to the discovery of new therapeutic targets for a host of cardiovascular diseases that afflict our older patients."

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Dr. Roh and his team have recently uncovered evidence that the activin type II (ActRII) pathway, a catabolic pathway that regulates muscle growth, plays an important role in heart disease and aging. Their findings, published in Science Translational Medicine, also showed that blocking this pathway with clinical-grade reagents could restore the function of the failing heart in multiple animal models of heart failure.

"Identifying new therapeutic targets for heart failure is a primary goal of our research group," he says. "When we saw the profound effects we were having on cardiac function with inhibiting the ActRII pathway, we got excited."

Identifying Biological Processes that Change in Human Aging

To begin to examine the relationship between aging and heart failure, Dr. Roh, Anthony Rosenzweig, MD, chief of the Cardiology Division and co-director of the Corrigan Minehan Heart Center, and colleagues performed a proteomics analysis of blood samples from the Framingham Heart Study, which included nearly 900 people aged in their 20s to late 80s. Of the >1000 proteins assayed, follistatin-like 3 (FSTL3), was one of the top proteins that increased with age in this healthy community cohort.

"FSTL3 is a downstream target of ActRII signaling, and its expression essentially increases whenever this pathway is activated in cells. We used this unique feature of FSTL3 to give us insights into how the ActRII pathway was being regulated in people as they age or develop disease," Dr. Roh says.

The ActRII pathway is quite complex. It consists of multiple receptors that bind a diverse spectrum of ligands, which are part of the TGF-β superfamily of proteins. To determine which of these ligands was likely causing the increase in circulating FSTL3 levels seen in older adults, they performed a correlation analysis with some of the major ActRII ligands and found that only activins positively correlated with FSTL3. Activins bind to ActRII receptors and help control and facilitate cellular growth and survival processes and have been shown to increase in heart failure.

The "TAVR Population": Examining the Role of ActRII Signaling in Heart Failure in Older Patients

To determine if this age-related increase in ActRII pathway activity contributes to heart failure, Dr. Roh and Dr. Rosenzweig's team looked at the "TAVR population"—many of whom are frail older adults who develop heart failure from their severe aortic stenosis. Geriatrics literature describes frailty as a clinical phenotype of diminished reserve capacities that people develop as they age.

"We use frailty not just as a prognostic factor in cardiovascular disease, but also as a clinical phenotype of accelerated biological aging," says Dr. Roh. "We believe there are likely biological processes intrinsic to aging and frailty that are driving the increased risk of heart disease as we get older, and that's the part we're trying to get at."

Indeed, when they measured FSTL3 and activin levels in older TAVR patients, they found that they not only increased with age and frailty, but also correlated with heart failure severity and other clinical biomarkers of heart failure, including brain natriuretic peptide (BNP).

Proving Causality in Heart Failure Animal Models

The next step was to determine if the observed increases in ActRII pathway activity functionally contribute to cardiac function in heart failure. To do this, Dr. Roh's team took a gain- and loss-of-function approach, first activating the ActRII pathway to see if it induced impairments in cardiac function.

"We increased the circulating levels of activins in the blood of healthy, young mice to see what would happen to their hearts," says Dr. Roh. "By doing this, we activated this catabolic pathway and not only induced pathologic atrophy, but also dysfunction in the contractile and relaxation properties of the heart. That gave us a hint that activation of the pathway is probably detrimental to cardiac function."

They then did the exact opposite by inhibiting the pathway in multiple mouse models of heart failure including:

• Transverse aortic constriction (a model of aortic stenosis)
• Genetic dilated cardiomyopathy
• Older mouse models of heart failure with preserved ejection fraction (HFpEF)

The researchers treated the mice with a clinical-grade antibody that directly blocks the ActRII receptors. "In all of these models, we saw a pretty dramatic improvement in cardiac function," says Dr. Roh. "Even in our models of HFpEF, in which we have no effective treatments for yet, we saw improvements in their cardiac performance and exercise capacity."

To further confirm the potential benefits of inhibiting this pathway in heart failure, they also used soluble ligand traps, a different formulation of an ActRII pathway inhibitor, and saw similar results. As a final proof of principle, researchers genetically knocked out these receptors in the heart and reported a similar functional phenotype.

"Seeing similar results in multiple heart failure models with multiple approaches to antagonizing this pathway really convinced us that the ActRII pathway could possibly be a new therapeutic target for heart failure," says Dr. Roh.

Reexploring the Role of SERCA2a in Cardiomyocyte Function

SERCA2a is a protein critical to heart muscle function. Prior research from Dr. Rosenzweig's group has suggested that restoring SERCA2a levels can restore a failing cardiomyocyte's function.

Dr. Roh's team sought to understand the underlying mechanisms of their findings by doing transcriptome analysis on isolated cardiomyocytes in which the ActRII pathway had been perturbed.

"One of the things that popped up in our analysis was a reduction in cardiac contractility and impairment of calcium handling," says Dr. Roh. "And that's what happens when SERCA2a levels decline. SERCA2a moves calcium back into the sarcoplasm, enabling the cardiomyocytes to relax and contract properly. We found that when you overactivate this pathway, you activate the proteasome, which breaks down SERCA2a levels. We were able to partially restore SERCA2a levels in the failing heart by inhibiting this pathway, which is probably one of the reasons manipulating this pathway may be beneficial in heart failure."

Multidisciplinary Research Will Lead Future Findings

The investigators at Mass General leveraged their multidisciplinary expertise, utilizing state-of-the-art high throughput screening technology for human discovery, clinical validation with rigorous phenotyping and advanced imaging in patients with frailty and heart failure, and animal models to advance the understanding of heart failure and aging.

"This is an especially exciting time in cardiovascular biology and research," Dr. Roh says. "Being part of these amazing multidisciplinary teams enables us to flow back and forth between the bedside and the bench to enable new discoveries that will hopefully lead to much-needed new therapies for our patients."

Learn more about the Heart Failure and Cardiac Transplant Program

Refer a patient to the Corrigan Minehan Heart Center