C-Reactive Protein: The Quintessential Marker of Systemic Inflammation in Coronary Artery Disease-Advancing toward Precision Medicine

Abstract

Atherosclerotic cardiovascular disease (CVD) remains the leading cause of mortality worldwide. While conventional risk factors have been studied and managed, CVD continues to pose a global threat. Risk scoring systems based on these factors have been developed to predict acute coronary syndromes and guide therapeutic interventions. However, traditional risk algorithms may not fully capture the complexities of individual patients. Recent research highlights the role of inflammation, particularly chronic low-grade inflammation, in the pathogenesis of coronary artery disease (CAD). C-reactive protein (CRP) is an inflammatory molecule that has demonstrated value as a predictive marker for cardiovascular risk assessment, both independently and in conjunction with other parameters. It has been incorporated into risk assessment algorithms, enhancing risk prediction and guiding therapeutic decisions. Pharmacological interventions with anti-inflammatory properties, such as statins, glucagon-like peptide-1 agonists, and interleukin-1 inhibitors, have shown promising effects in reducing both cardiovascular risks and CRP levels. This manuscript provides a comprehensive review of CRP as a marker of systemic inflammation in CAD. By exploring the current knowledge surrounding CRP and its implications for risk prediction and therapeutic interventions, this review contributes to the advancement of personalized cardiology and the optimization of patient care.

Keywords: C-reactive protein; atherosclerotic cardiovascular disease; coronary artery disease; inflammation; personalized cardiology; precision medicine.

Figure 1

Proposed mechanistic models of ACS. (A) Vasospasm-induced ACS: Vasospasm, known to occur in epicardial arteries, can also impact coronary microcirculation, triggering ACS, such as unstable angina, independently of inflammation. (B) Plaque erosion-induced ACS: Plaque erosion is increasingly recognized as a contributor to ACS, particularly the non-ST-segment elevation MI. The thrombi formed over eroded intimal patches exhibit characteristics of platelet-rich structures, termed the “white” thrombus. (C) Non-inflammatory plaque rupture-induced ACS: Some atheromata may experience plaque rupture without exhibiting extensive intimal macrophage collections or elevated circulating CRP levels. This type of plaque rupture leads to the formation of fibrin-rich “red” thrombi. (D) Inflammatory plaque rupture-induced ACS: Plaque rupture has conventionally been considered the primary cause of ACS, especially the ST-segment elevation MI. It often occurs in plaques featuring local inflammation marked by macrophage infiltration and systemic inflammation indicated by elevated CRP levels in the blood.

Figure 2

Mechanisms of CRP in atherosclerotic CVD. CRP, predominantly synthesized in the liver under the influence of proinflammatory cytokines such as IL-6, IL-1β, and TNF, plays a pivotal role in the progression of atherosclerotic CVD. Various single nucleotide variants (SNVs) can modulate CRP production. Once released into circulation, CRP exists in a pentameric form and exhibits recognition and binding capabilities to danger-associated molecular patterns (DAMPs), such as the phosphocholine found in apoptotic debris, as well as pathogen-associated molecular patterns (PAMPs), such as the lipopolysaccharide in the membrane of gram-negative bacteria. Upon activation, CRP undergoes a conformational change into functionally active monomers, leading to the initiation of the complement cascade and activation of inflammatory macrophages (M1 phenotype). In the context of chronic inflammation, these stimuli become detrimental and facilitate the deposition of oxidized low-density lipoproteins (oxLDL) and lipid-containing foam cells within the vascular sub-endothelium. The formation of cholesterol crystals in atheromatous plaques further enhances the activation of inflammasomes, which are PAMP and DAMP recognition receptors. Consequently, this process leads to increased production of IL-1β and IL-18. This inflammatory microenvironment triggers heightened production of chemoattractants and adhesion molecules while concomitantly reducing the production of nitric oxide and other vasodilatory factors. Such disruption of vascular endothelial homeostasis results in an augmented atherosclerotic burden and the development of CAD.