Can preventing inflammation improve heart and brain health?

When healing injuries or warding off harmful bacteria, the body’s immune system activates an inflammatory response. 

If unchecked or overactive, inflammation can bring about more harm than good — eventually leading to disease.

Researchers continue to study the body’s response to inflammation, seeking to understand the “crosstalk” between the heart and brain and how inflammation drives different diseases in both organs. 

In April 2024, University of Michigan and two other institutions were collectively awarded $15 million to participate in the American Heart Association’s Strategically Funded Research Network on Inflammation in Cardiac and Neurovascular Disease. 

The collaboration will focus on developing strategies for recognizing and treating inflammation.

Michigan Medicine will partner with Massachusetts General Hospital and Oakland University to specifically examine the factors that drive inflammatory processes associated with aging and obesity.

“Inflammation is a serious risk factor behind life-threatening cardiac and neurovascular diseases,” said Anthony Rosenzweig, M.D., leader of the multi-project center and director of the Stanley and Judith Frankel Institute for Heart and Brain Health.

“The hope is that our research will close knowledge gaps and lead to new methods for preventing or treating the damaging inflammation associated with aging and unhealthy lifestyles.”

To improve understanding of this health issue, Rosenzweig and Eva L. Feldman, M.D., Ph.D., director of Michigan Medicine’s NeuroNetwork for Emerging Therapies and principal investigator for one of the projects, answer key questions about the cause and impact of inflammation in hearts and brains, as well as what researchers are doing to address them.

How does inflammation contribute to heart and brain dysfunction?

Rosenzweig: When inflammation persists or is overly active, it can damage healthy cells, tissues and organs. Ultimately, this can contribute to heart and brain dysfunction and even life-threatening illnesses. 

One of the most common ones we deal with – and a leading cause of morbidity in the United States – is heart failure. 

Inflammation has long been known to contribute to blockages in the blood vessels that supply the heart, contributing to heart attacks. 

More recently, we’ve recognized that inflammation also directly affects the heart muscle, contributing to heart failure. The initial cause of that inflammation could be a heart attack, metabolic diseases such as obesity or diabetes, or something else. 

The inflammation can perpetuate and exacerbate ongoing dysfunction.

Feldman: The same can be said for brain dysfunction. 

People think of the heart and brain as very different organs, but both share very similar features, such as an extremely limited capacity for regeneration. 

Like the heart, the brain is very vulnerable to damage because it cannot self-renew as readily as some tissues, such as skin. 

Chronic inflammation breaks down critical pathways in the brain and causes injury to brain tissue which accumulates with time, disrupting normal function and leading to cognitive impairment. 

What diseases are linked to inflammation?

Rosenzweig: Inflammation is linked to many different conditions. 

During the COVID pandemic, we saw many people develop acute respiratory distress syndrome. In many cases, much of the damage was mediated by the immune response to the virus. But inflammation is tied to a whole host of diseases, from diabetes and hepatitis to autoimmune diseases such as systemic lupus or rheumatoid arthritis. 

It also contributes to heart failure, heart attack, cognitive impairment and many forms of dementia. 

Virtually every organ in the body can be affected by inflammatory diseases. 

We also know that metabolic diseases, such as obesity and diabetes, are themselves drivers of inflammation, in part because adipose tissue secretes inflammatory cytokines. 

Moreover, as we age, chronic, low-grade dysregulation of inflammatory pathways, called inflammaging, is commonly seen.

What gaps in knowledge are there in recognizing and treating inflammation?

Rosenzweig: We really need to understand on a much more granular level which proteins are causing chronic inflammation and how we can best control these pathways. 

One has to be very thoughtful about where to intervene. 

We still need inflammation to fend off infections, so picking the best therapeutic targets and striking the right balance is key.

Feldman: I agree that learning how to fine tune and control it so we can dampen the bad parts of the inflammatory response while not giving give up the protective side is a real challenge for the medical field. 

The hope is that learning how to control responses in one setting, whether it's the heart or the brain, may give us insights into how to control it in other parts of the body.

What does Michigan Medicine hope to discover about inflammation?

Rosenzweig: As Dr. Feldman said, our overarching hypothesis is that the heart and brain share a vulnerability to metabolic stress and aging due to their long-lived cells with a very limited capacity for regeneration. 

As people age, cells undergo this process called senescence, a state where cells stop dividing and secrete inflammatory molecules. 

This process is accelerated by metabolic stress, such as obesity or diabetes.

We think that the heart can secrete proteins that affect the brain and vice versa, so our hope is to better understand the crosstalk between the heart and brain. 

If we can identify the key proteins involved in this process, then we can develop ways to intervene.

Feldman: Another key for developing ways to intervene is to identify specific cell types that perpetuate chronic inflammation during aging and metabolic stress. 

In the brain, we are interested in focusing on a cell type called microglia, the immune cells of the brain. 

During aging and metabolic stress, the brain microglia release proteins linked to inflammation, which can damage the brain, and, potentially through crosstalk, the heart. 

What is the methodology for Michigan Medicine’s research?

Rosenzweig: There are three key components to this collaborative center, two of which are based at University of Michigan. 

Dr. Feldman’s lab and my own will undertake complementary studies examining inflammatory mechanisms in both the brain and the heart, looking at microglial cells in the brain, and their counterpart in the heart, monocytes and macrophages.

We’re using overlapping models in which animals are placed on a high-fat diet to induce metabolic stress and observing what happens as they age. 

This is a common model of heart failure that we've been studying, as well as a common model of cognitive decline or dementia that Dr. Feldman has been studying. 

Feldman: By bringing those two efforts together, we can collaboratively identify the common and distinct mechanisms in each organ as well as the signals going back and forth between the two organs that may make things worse. 

We’ll also be experimenting with drug and lifestyle interventions like exercise to examine their potential to mitigate – or even reverse – these processes.

Rosenzweig: The third project, led by Drs. Greg Lewis and Sawalla Guseh, is a clinical trial taking place at Massachusetts General Hospital. 

It builds upon our research of a new treatment that inhibits inflammatory senescence molecules. 

The trial will examine whether this intervention alone or in combination with exercise effectively reduces inflammation and what the impact is on heart failure and cognitive function. 

The trial will be conducted on patients with an unhealthy body weight and heart failure. 

The hope is that we will see metabolic benefits without losing the skeletal muscle mass.

What is the end goal for this research study?

Feldman: First, we want to test the hypotheses that there are common biological pathways driving disease in the heart and brain as well as signals that travel between the organs. 

Second, we hope to identify key pathways and methods for intervention. 

And third, we hope that this clinical trial will provide favorable results, encouraging further investigation of this entirely new approach to therapy for heart and brain diseases. 

The goal would be to lay a foundation for a larger trial examining efficacy on hard clinical endpoints of this intervention in heart failure and cognitive decline.

How will this research benefit patients in the future?

Rosenzweig: The ultimate goal is improving quality of life and saving patients’ lives. 

Inflammation and the diseases associated with it are a large and growing unmet clinical need. 

We hope to develop both a deeper understanding and new therapeutic approaches that can positively impact these conditions that affect millions of Americans. 

Moving forward, not only could this help patients, but it would also open the door for more researchers to develop interventions that impact senescence and inflammatory pathways. 

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