Which cells arrive first at the site of a myocardial infarction (MI)?

Neutrophils Arrive First After Myocardial Infarction

Neutrophils are the first cells to arrive at the site of myocardial infarction, initiating the inflammatory response that is essential for cardiac repair. 1 This initial neutrophil infiltration begins the cascade of cellular responses that ultimately leads to clearing of necrotic tissue and cardiac wound healing.

Cellular Timeline After Myocardial Infarction

First Responders: Neutrophils

• Neutrophils arrive within minutes to hours after the onset of ischemia
• They initiate the pro-inflammatory response by:
  • Upregulating cytokines and chemokines (particularly interleukin-1 beta)
  • Releasing pre-formed proteases (matrix metalloproteinases -8 and -9)
  • Degrading existing extracellular matrix to clear necrotic tissue 2

Secondary Response: Monocytes and Macrophages

• Following neutrophil infiltration, monocytes respond to chemotactic factors
• Monocytes differentiate into macrophages at the injury site
• Macrophages perform critical functions including:
  • Removing necrotic cardiac myocytes
  • Clearing apoptotic neutrophils
  • Secreting cytokines, chemokines, and growth factors 3

The Dual Role of Neutrophils in Cardiac Repair

Neutrophils play a complex role in post-MI healing, with both damaging and reparative functions:

1. Initial Pro-inflammatory Phase:

   • Neutrophils release proteolytic enzymes that can damage viable tissue
   • They produce reactive oxygen species contributing to oxidative stress

2. Transition to Reparative Phase:

   • Neutrophils shift to a reparative phenotype that promotes inflammation resolution
   • They release neutrophil gelatinase-associated lipocalin (NGAL), which helps polarize macrophages toward a reparative phenotype 4
   • They facilitate scar formation and cardiac repair

Pathological Progression After MI

According to pathological classification, myocardial infarction progresses through distinct phases:

• Evolving phase (≤6 hours): Characterized by initial neutrophil infiltration
• Acute phase (6 hours-7 days): Marked by presence of polymorphonuclear leukocytes (primarily neutrophils)
• Healing phase (7-28 days): Characterized by mononuclear cells and fibroblasts, with absence of neutrophils
• Healed phase (≥29 days): Manifested as scar tissue without cellular infiltration 1

Clinical Implications

Understanding the cellular response after MI has important clinical implications:

• Timing of Interventions: Therapeutic strategies targeting neutrophils must be carefully balanced, as complete depletion of neutrophils can impair cardiac repair 4
• Sex-Specific Differences: Recent evidence suggests sex-specific differences in neutrophil signaling after MI, which may influence treatment approaches 5
• Biomarker Significance: The presence of neutrophils correlates with elevated cardiac biomarkers, particularly troponins, which indicate myocardial necrosis 1

Potential Pitfalls in Clinical Management

• Over-aggressive anti-inflammatory therapy: While limiting acute neutrophil-driven inflammation might reduce immediate damage, it could interfere with the healing response and cardiac remodeling
• Failure to recognize the biphasic role of neutrophils: Both excessive neutrophil activity and complete neutrophil depletion can worsen outcomes 6
• Overlooking the importance of the neutrophil-macrophage interaction: Neutrophils are crucial for polarizing macrophages toward a reparative phenotype 4

The orchestrated cellular response following MI, beginning with neutrophil infiltration, represents a finely balanced process that is essential for optimal cardiac repair and prevention of adverse remodeling.