AHA 2023: Strategically Focused Research Network (SFRN) on Inflammation in Cardiac and Neurovascular Disease

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UArizona may submit one pre-application.

AHA Membership Requirement: Any individual applying as a Center Director or a Project Principal Investigator (PI) must be an AHA Professional Member before submitting a full proposal. (Membership is not required to submit a pre-proposal.) Join or renew when preparing an application in ProposalCentral, online, or by phone at 301-223-2307 or 800-787-8984. Membership processing may take 3-5 days; do not wait until the application deadline to renew or join.

Required Pre-Proposal 

Each Center Director is required to send a pre-proposal USE THIS LINK to provide the following:

• Name and institution of the Center Director and each Project PI
• Center title, and title and performance site of each proposed project

If required, the mechanism through which partnering requirements are being met. See “Additional Expectations and Opportunities” and “Institutional Eligibility/Location of Work” sections.

As part of the required Pre-Proposal, if the submitting institution or a partnering institution is not a research-intensive institution of higher learning, the lead for that institution must upload a letter from a Senior Institutional Official (e.g., president, provost, dean, etc.) indicating they meet the definition of a non-research-intensive institution as stated in the “Additional Expectations and Opportunities” section. 

AHA staff will review for compliance. A non-complying institution will not be permitted to submit a full proposal. This administrative review is part of the Pre-Proposal process, which is required and, though rare, may prevent an applicant from moving forward. Even though the Pre-Proposal is required, each Center and Project applicants should begin planning and designing their applications before the Pre-Proposal deadline to maximize the amount of time available to develop their full proposal.

Purpose
The American Heart Association (AHA) announces this Request for Proposals for the Strategically Focused Research Network (SFRN) on Inflammation in Cardiac and Neurovascular Disease.

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.