Strategically Focused Research Network (SFRN) on Inflammation in Cardiac and Neurovascular Disease

These four-year awards include a collaborative research project three groups, called centers. To further the American Heart Association’s commitments to expanding diversity in clinical research, each of the centers will work in conjunction with an academic institution that primarily serves individuals who are underrepresented in science

The research centers and the projects include:

Northwestern University Chicago Campus – Led by center director Matthew J. Feinstein, M.D., M.Sc., FAHA, associate professor of medicine (cardiology) and director of the Clinical and Translational ImmunoCardiology Program at Northwestern’s Bluhm Cardiovascular Institute, research teams at Northwestern University, collaborating with a team from Chicago State University, will undertake three different projects focused on inflammation in heart failure with preserved ejection fraction (HFpEF). This type of heart failure is marked by excess inflammation, accounts for more than half of heart failure cases in the U.S. and carries a significant public health burden: 50% of people diagnosed with HFpEF die within 5 years. Unfortunately, few treatments exist for HFpEF, and effective ways to target inflammation in HFpEF are limited. In these complementary projects, the researchers aim to determine how inflammation may be targeted at a cellular level to prevent and treat HFpEF. They will focus on immune cells, which crucially determine whether inflammation persists unchecked or resolves. Specifically, they will study ways that immune cells are primed by metabolic and other stressors to turn problematic inflammation on or off in various contexts, as well as how this impacts heart dysfunction and HFpEF. They will also investigate how existing and novel approaches targeting metabolism and immune cell function affect HFpEF onset and progression. The ultimate goal of these efforts is to develop specific, patient-relevant means of targeting inflammation to curb HFpEF.

University of Michigan – Anthony Rosenzweig, M.D., FAHA, director of the Stanley and Judith Frankel Institute for Heart and Brain Health at Michigan Medicine, the academic medical center of the University of Michigan, will serve as the director of a collaborative research effort between Michigan Medicine and Massachusetts General Hospital. These research teams, in collaboration with a team from Oakland University in Rochester Hills, Michigan, will study the driving forces behind inflammatory processes linked to aging and obesity and how to prevent inflammation that could lead to heart failure, dementia and other diseases. They will study mechanisms behind and potential treatments for cell senescence, a process that occurs with aging and unhealthy lifestyles that results in damaged cells. Inflammation from senescent cells can harm other cells, starting a cycle of inflammation that can damage the heart, brain and other organs. They are studying cells called microglia – the brain’s main immune cells – and their counterpart, monocytes and macrophages, in the heart. The combination of aging with an unhealthy lifestyle can lead to dysfunction of these cells and inflammation in both the heart and the brain. These researchers want to understand this process better and learn how to prevent or lessen the inflammatory effects. They are expanding their research of a new investigational treatment that inhibits a pathway regulating metabolism and inflammation, as well as cardiac and skeletal muscle function. Early research suggests that the investigational treatment lessens inflammation, improves immune cell function and improves heart function. The proposal includes a first-ever clinical trial of this inhibitor for patients with unhealthy body weight and heart failure with preserved ejection fraction.

University of Pittsburgh – Led by center director Stephen Y. Chan, M.D., Ph.D., FAHA, professor of medicine (cardiology) and director of the Vascular Medicine Institute, the University of Pittsburgh research teams, in collaboration with a team from Prairie View (Texas) A&M University, will conduct three different projects aimed at identifying and treating interrelated conditions of brain and vascular pathology. They will specifically look at how lysosomes, components of cells that contain digestive enzymes and dispose of excess or worn-out cell parts, control inflammation in blood vessel diseases like heart attacks and brain diseases like Alzheimer’s disease. They will also work to develop new lysosomal medications by testing whether changes in a person’s DNA and blood related to the lysosome can predict vascular disease and dementia and response to anti-inflammatory therapy. Additionally, these researchers will study cellular mechanisms that impact memory in hopes of developing new medications to boost brain function for people who have experienced a heart attack.

Link to AHA Newsroom for announcement of the awardees.

The Role of Inflammation in Cardiac and Neurovascular Disease

Throughout the body, inflammation plays a crucial role in maintaining tissue homeostasis and initiating appropriate immune responses against pathogens or injury. However, dysregulation of inflammatory processes can lead to detrimental effects, contributing to the development and progression of many disease states, such as autoimmune conditions, cancer, diabetes, kidney disease and liver disease.¹

The heart and nervous system are also subject to disease with dysregulation of the inflammatory system. Inflammatory myocarditis, characterized by inflammation of the myocardium, is more likely to occur in males compared to females.² It is most commonly triggered by viral infection; triggering viruses include adenoviruses, enteroviruses, parvoviruses and coronaviruses (including SARS-CoV-2), among others.³ Less commonly, myocarditis is caused by bacterial or fungal infection or autoimmune diseases. Of more recent note, it was discovered during the COVID-19 pandemic that vaccines developed against SARS-CoV-2, particularly those using mRNA technology, elicited myocarditis in a subset of vaccine recipients.⁴ The highest incidence (approximately 50 / 100,000) was found in men under 40.

Myocarditis can be subclassified based on a number of characteristics. The most prominent symptoms are chest pain and dyspnea,⁵ and in many cases, myocarditis may resolve on its own. One notable exception is fulminant myocarditis, a rare and severe form of myocarditis that is responsible for a high proportion of cardiac-related deaths in young individuals.⁶ Acute myocarditis is defined as that for which symptoms are of recent onset, generally within a month or so. Inflammatory processes associated with myocarditis, such as infiltration of immune cells, release of pro-inflammatory cytokines, and oxidative stress, can lead to myocyte damage, fibrosis, and impaired contractility.^3,7-8 Myocarditis that is associated with cardiac dysfunction and remodeling of the ventricle is referred to as inflammatory cardiomyopathy, a condition that is typically irreversible. It may result in arrhythmias, ventricular dysfunction or heart failure and requires lifelong therapy and/or heart transplant.

Within the nervous system, inflammation has been implicated in an array of pathologies, such as Alzheimer’s disease, Parkinson’s disease, and multiple sclerosis.^9-10 Inflammation also plays a prominent role in stroke.^11-13 A robust neuroinflammatory response is initiated following an ischemic event. Sex differences are also observed with stroke, with the risk being higher for females than males.¹⁴ The primary cause of this neuroinflammation is the activation of immune cells in the brain, including microglia and astrocytes. These cells are responsible for defending the brain against pathogens and injuries. However, under certain conditions, they can become overactivated and release inflammatory molecules. Neuroinflammation can have both beneficial and detrimental effects. In acute situations, neuroinflammation helps clear pathogens, promote tissue repair, and support the restoration of normal brain function. However, chronic or excessive neuroinflammation can damage neurons, impair synaptic communication, break down the blood-brain barrier, and disrupt the delicate balance of the brain's environment.¹¹

Cardiotoxicity

Cardiotoxicity describes a condition wherein a decrease in cardiac function results from administration of drugs or other agents. Currently, the term is largely identified with changes in cardiovascular function resulting from treatment with a number of cancer therapies. Whereas a decrease in left ventricular ejection fraction is the cardiac parameter most closely aligned with cardiotoxicity, additional cardiac effects (e.g., left ventricular systolic dysfunction, angina, and acute coronary syndrome) may also be characterized as cardiotoxicity.¹⁵ 

There are several potential mechanisms underlying cardiotoxicity of chemotherapeutic agents, including inflammation. For example, use of chemotherapeutics of the anthracycline class, widely prescribed because of their efficacy against both solid and hematologic tumors, is associated with a high incidence of cardiotoxicity.¹⁶ Despite this effect of anthracyclines being described decades ago, the mechanism(s) underlying cardiotoxicity are not fully elucidated. Studies in more recent years do suggest, however, that at least part of the cardiotoxic actions of anthracyclines are related to inflammation.¹⁷ In addition, pre-clinical studies assessing effects of anti-inflammatory agents against anthracycline-induced cardiotoxicity have shown favorable results.^18-19 Targeting inflammation thus holds promise for preventing or mitigating cardiotoxic effects of this class of chemotherapeutic.

More contemporary cancer treatments also elicit adverse cardiac effects. Immune checkpoint inhibitors (ICIs), a new and promising class of anti-cancer drugs, may elicit a severe form of myocarditis.²⁰ Whereas the incidence is relatively low, the mortality rate is high, due in part to the fact that many individuals present with a fulminant-like form of myocarditis. The mechanism underlying ICI-induced myocarditis remains unclear. The promise of this new class of cancer treatment will not be fully realized unless the mechanism is identified, which will facilitate therapeutic strategies to prevent or mitigate this severe adverse effect.

While our understanding of the role inflammation plays in cardiac and brain dysfunction has grown considerably in recent years, several hindrances remain that preclude improved recognition and treatment of these conditions. For instance, significant gaps remain in understanding of the downstream signaling events and potential crosstalk; development of new animal and in vitro models would support these needs. In addition, notable opportunities for optimization of diagnostic capabilities exist, such as identification and assessment of biomarkers with improved specificity and development of improved imaging techniques. Clinical trials designed to assess outcomes more specifically for distinct types and/or stages of inflammatory conditions are also needed.