Modulation of Inflammation in Cardiac Function after Myocardial Infarction

Behrooz G Sharifi; Prediman K Shah

doi:10.37871/jbres2120

ISSN: 2766-2276

Medicine Group 2025 June 16;6(6):661-665. doi: 10.37871/jbres2120.

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Review Article

Modulation of Inflammation in Cardiac Function after Myocardial Infarction

Behrooz G Sharifi* and Prediman K Shah

Oppenheimer Atherosclerosis Research Center, Smidt Heart Institute at Cedars Sinai Medical Center, Los Angeles, CA 90048

*Corresponding authors: Behrooz G Sharifi, Smidt Heart Institute at Cedars Sinai Medical Center, AHSP #9114, 8700 Beverly Blvd, Los Angeles, CA 90048 E-mail:

Received: 03 June 2025 | Accepted: 13 June 2025 | Published: 16 June 2025

How to cite this article: Sharifi BG, Shah PK. Modulation of Inflammation in Cardiac Function after Myocardial Infarction. J Biomed Res Environ Sci. 2025 Jun 16; 6(6): 661-665. doi: 10.37871/jbres2120, Article ID: jbres1757

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Introduction

Acute Myocardial Infarction (MI) remains a leading cause of death worldwide. Although reperfusion therapies have improved survival following the initial ischemic event, many patients are still at elevated risk of developing heart failure due to a process known as ventricular remodeling [1]. Consequently, there is a pressing need for new therapies that can limit infarct size and prevent maladaptive remodeling and heart failure.

Following MI, the heart undergoes a robust inflammatory response, initially marked by the infiltration of neutrophils, which are rapidly cleared, followed by the sustained presence of pro-inflammatory monocytes and macrophages [2,3]. Over time, these monocytes can transition into reparative phenotypes [2,4]. The prevailing hypothesis is that uncontrolled inflammation drives disease progression, and targeting pro-inflammatory pathways may protect against adverse remodeling after MI reviewed in [5,6].

However, despite this rationale, numerous anti-inflammatory therapies have failed to demonstrate clinical benefit. Corticosteroids and other agents have shown limited or no efficacy in fibrotic diseases such as idiopathic pulmonary fibrosis, where inflammation does not correlate well with disease stage or prognosis, and anti-inflammatory treatment has not improved outcomes [7]. Similarly, clinical trials aimed at reducing cardiac inflammation have yielded disappointing results [8-10]. For instance, early studies suggested TNFα inhibition with etanercept might enhance cardiac function [10], but larger trials were terminated for lack of efficacy [9]. Another trial using infliximab, a chimeric monoclonal anti-TNFα antibody, was also discontinued [9].

In a meta-analysis of patients with acute myocarditis, corticosteroid treatment was associated with improved left ventricular ejection fraction but did not affect survival [11]. Overall, interventions targeting inflammation-including those controlling the broader immune response [12-13] - have not translated into improved clinical outcomes in heart failure. As a result, current clinical guidelines advise against the use of steroids and Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) in the acute and early post-ST-Segment Elevation Myocardial Infarction (STEMI) phase, due to concerns about potential harm [14].

While the pathogenesis of MI is primarily vascular, the immune system, especially the innate immune arm, plays a critical role in orchestrating the response to myocardial injury. This response is multifaceted, involving the immediate recognition of tissue damage, the recruitment of immune cells, and the regulation of healing and scar formation. However, dysregulation of these processes can result in adverse cardiac remodeling and the progression to heart failure.

Innate Immune Cell Recruitment and Function

The initial immune response following MI is marked by a tightly regulated infiltration of innate immune cells. Neutrophils are the first to arrive, infiltrating the infarcted myocardium within hours of injury. Their primary functions include phagocytosis of necrotic debris, generation of Reactive Oxygen Species (ROS), and secretion of proteolytic enzymes. Neutrophils can also form Neutrophil Extracellular Traps (NETs) to help contain local inflammation [15,16]. Beyond their direct antimicrobial actions, neutrophils play a critical role in orchestrating the subsequent immune response by modulating the activity of both innate and adaptive immune cells, including macrophages and lymphocytes [15].

Neutrophils exhibit functional heterogeneity and can be classified into two major phenotypes: pro-inflammatory N1 (Ly6G⁺ CD206⁻) and anti-inflammatory N2 (Ly6G⁺ CD206⁺) subtypes. N1 neutrophils express high levels of inflammatory mediators such as IL-1β, IL-12a, and TNF-α, and are characterized by a CD49d^high CD11b^low surface expression pattern. In contrast, N2 neutrophils express anti-inflammatory markers like IL-10 and display a CD49d^low CD11b^high phenotype. In mouse models of MI, N1 (CD206⁻) neutrophils dominate during the first 7 days post-infarction, while N2 (CD206⁺) neutrophils gradually increase between days 5 to 7 [17].

Following neutrophil infiltration, monocyte are recruited to the injured myocardium in response to chemokines such as CCL2 [18]. Fate mapping analyses and lineage tracing experiments have indicated that tissue macrophages in many organs are of early embryonic origin [19-21]. Monocytes are a heterogeneous population of myeloid cells that originate from progenitors in the bone marrow, and traffic via the bloodstream to peripheral tissues. Monocytes are bone marrow-derived circulating cells that localize to injured and inflamed tissues and differentiate locally into diverse myeloid cell populations [22]. Early after MI, pro-inflammatory (M1-like) macrophages predominate, contributing to further debris clearance and cytokine production. As the healing phase progresses, a shift toward reparative (M2-like) macrophages supports tissue repair and scar formation (Figure 1).

Recent studies also suggest that monocytes and macrophages possess the ability to develop innate immune memory, a concept traditionally reserved for adaptive immune cells such as T and B lymphocytes. This form of "trained immunity" enables innate cells to respond more robustly upon re-exposure to the same or similar stimuli. This enhanced responsiveness is mediated by epigenetic and transcriptional reprogramming triggered by the initial inflammatory encounter [23,24]. These findings underscore the complexity and adaptability of the innate immune system in the context of myocardial injury and repair.

Dendritic cells contribute to the post-MI immune response by processing and presenting antigens, thereby serving as a critical link between the innate and adaptive immune systems. In parallel, the complement system plays a significant role in mediating inflammation following acute MI. When dysregulated, complement activation exacerbates tissue damage, contributing to larger infarct sizes and worse clinical outcomes [25]. After MI, the complement cascade is activated, promoting opsonization of necrotic cells, recruitment of immune cells, and the production of pro-inflammatory cytokines.

Initiation of the Innate Immune Response

The innate immune response to MI is initiated almost immediately following ischemic injury. As cardiomyocytes undergo necrosis, they release Damage-Associated Molecular Patterns (DAMPs), including High-Mobility Group Box 1 (HMGB1), ATP, mitochondrial DNA, and heat shock proteins. These DAMPs are recognized by Pattern Recognition Receptors (PRRs), such as Toll-Like Receptors (TLRs) and NOD-Like Receptors (NLRs), which are expressed on resident and circulating immune cells, including macrophages, dendritic cells, and neutrophils.

Among the PRRs, Toll-Like Receptor 4 (TLR4) plays a pivotal role in post-MI inflammation by activating downstream signaling pathways, notably NF-κB, leading to the production of pro-inflammatory cytokines such as Tumor Necrosis Factor-α (TNF-α), Interleukin-1β (IL-1β), and interleukin-6 (IL-6). In parallel, activation of the NLRP3 inflammasome facilitates the maturation and secretion of IL-1β, further amplifying the inflammatory cascade and contributing to adverse cardiac outcomes [17,26].

Resolution of Inflammation and Tissue Repair

Timely resolution of inflammation is critical to preventing chronic inflammation and adverse cardiac remodeling after myocardial infarction. Key processes involved in this resolution phase include:

Efferocytosis – the clearance of apoptotic neutrophils by macrophages;
Macrophage phenotypic switching – the transition from a pro-inflammatory to a reparative (anti-inflammatory) phenotype; and
Secretion of reparative growth factors – such as Vascular Endothelial Growth Factor (VEGF) and Transforming Growth Factor-β (TGF-β), which promote angiogenesis and tissue repair.

Disruptions in any of these mechanisms can impair healing and contribute to pathological outcomes, including ventricular dilation, fibrosis, and the progression to heart failure.

Therapeutic Implications

The inflammatory response is essential for initiating tissue repair following MI. However, as previously discussed, clinical efforts to broadly suppress inflammation in MI patients have generally yielded disappointing results. In some cases, extensive anti-inflammatory interventions have even produced harmful effects. Therefore, rather than completely inhibiting inflammation, therapeutic strategies should aim to restore the balance between pro-inflammatory and reparative immune cell populations.

This approach involves either enhancing the body's intrinsic anti-inflammatory mechanisms or selectively inhibiting key pro-inflammatory pathways. The goal is to minimize the harmful effects of excessive inflammation while preserving its beneficial roles in tissue repair and remodeling [27,28].

A better understanding of innate immune mechanisms in MI has paved the way for more targeted therapies. For example, IL-1β inhibitors such as canakinumab have shown promise in reducing recurrent MI and cardiovascular mortality [28]. In addition, TLR antagonists and NLRP3 inflammasome inhibitors are being investigated as strategies to limit excessive inflammatory signaling. Modulating monocyte and macrophage recruitment, particularly through CCR2 antagonism, is another promising approach to fine-tune post-MI inflammation and promote optimal healing.

Conclusion

Innate immunity plays a pivotal role in the response to myocardial infarction, driving both the initial inflammatory reaction and subsequent tissue repair. However, dysregulation of this system can exacerbate cardiac injury and promote maladaptive remodeling. Ongoing research and the development of precisely targeted therapies hold promise for leveraging the beneficial aspects of innate immunity while minimizing its detrimental effects.