Prognostic Significance of High-Sensitivity C-Reactive Protein in Acute Myocardial Infarction: Cardiovascular Outcomes in Diabetic and Non-Diabetic Patients

Abstract

High-sensitivity C-reactive protein (hs-CRP) is one among the widely studied risk factors among systemic markers of inflammation with growing significance in the prognosis of acute myocardial infarction (AMI). This review integrates findings from various studies assessing the role of hs-CRP in predicting cardiovascular outcomes in AMI patients, with and without diabetes mellitus (DM). Elevated hs-CRP levels were consistently associated with increased risks of heart failure, arrhythmias, reinfarction, and mortality. Diabetic patients exhibited higher baseline hs-CRP levels and a greater incidence of complications. Notably, hs-CRP remained an independent predictor of major adverse cardiovascular events (MACE) across several studies, beyond traditional risk scores. These findings support the clinical utility of hs-CRP in early risk stratification and outcome prediction following AMI, particularly in patients with DM.

Keywords

Introduction

Inflammation is one of the main mechanisms in the pathogenesis of atherosclerosis, and the interest in the evaluation of inflammatory biomarkers in coronary artery disease (CAD) has been increasing over the last decade. Destabilisation of chronic artery plaques, which leads to acute coronary syndromes, has been associated with an inflammatory status [1]. Among the various inflammatory markers, high-sensitivity C-reactive protein (hs-CRP) has gained considerable attention for its utility in cardiovascular risk stratification. Hs-CRP is a hepatic acute-phase reactant, produced in response to interleukin-6 and other proinflammatory cytokines that reflects the degree of systemic inflammation—a key contributor to plaque instability and thrombosis in coronary artery disease (CAD) [1, 2, 3].  Acute myocardial infarction (AMI) remains a leading cause of morbidity and mortality worldwide, with inflammation playing a central role in its pathogenesis and prognosis [7]. Multiple studies have demonstrated that elevated hs-CRP levels during the acute phase of AMI are predictive of adverse short- and long-term cardiovascular outcomes, including recurrent myocardial infarction, heart failure, arrhythmias, and mortality, as acute hs-CRP phase levels before marked elevation of cardiac troponin I (cTnI) may make the body primed to respond to any necrotic or injured tissue. This depicts that in AMI patients there is a large variability in hs-CRP levels [1,4]. Prospective cohort and cumulative studies have supported that relatively high levels of hs-CRP in otherwise healthy individuals are linked to an increased risk of future heart attack, stroke, sudden cardiac death, and/or peripheral arterial disease, as well as cardiac events in CAD patients with colon cancer, complications of diabetes, and obesity [10]. hs-CRP has also been shown to correlate with infarct size, extent of coronary artery disease, and microvascular obstruction, further reinforcing its relevance in AMI management [3, 4]. Importantly, the impact of hs-CRP appears to be more pronounced in patients with diabetes mellitus (DM), a population already at risk for adverse cardiovascular outcomes. Elevated hs-CRP levels in AMI patients may reflect a variable combination of chronic and acute (due to the ongoing cardiac event) inflammation. Since DM is more frequently associated with some degree of chronic inflammation, it is possible that, in AMI patients with DM, hs-CRP has a different prognostic relevance as compared to their non-DM counterparts. Diabetic individuals often exhibit higher baseline levels of inflammation, which may contribute to larger infarct sizes, increased myocardial stress, and worse clinical trajectories post-AMI [2, 10, 15].  Recent healthcare-based studies and prospective cohort analyses support this association, highlighting the potential of hs-CRP as a tool for improved risk stratification in this subgroup. This review consolidates current evidence on hs-CRP’s prognostic value in AMI and explores its role in both diabetic and non-diabetic patients, highlighting its clinical applications in post-infarction management.

C-reactive protein (CRP) and High-sensitivity C-reactive protein (hs-CRP): Overview and Clinical Relevance

When it comes to the prognosis of STEMI, risk scores with a strong prognostic ability, particularly Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) scores, have been broadly used with the aim of early risk stratification. However, these scores do not include inflammatory markers [1, 3]. C-reactive protein (CRP) is a hepatic acute-phase reactant produced in response to inflammation. It is a plasma protein of the pentraxin family that plays a central role in the inflammatory cascade by promoting complement activation and facilitating the clearance of pathogens and necrotic tissue [1,3,5]. hs-CRP is a refined assay capable of detecting low-grade inflammation, making it particularly relevant in cardiovascular risk prediction. hsCRP levels are measured in plasma by immunochemistry, turbidimetry, or the nephelometry method. Unlike standard CRP, hs-CRP quantifies inflammation associated with atherosclerosis and plaque rupture, which are central to AMI pathogenesis [5,6]. Hs-CRP has also been shown to predict future cardiovascular events, including myocardial infarction, stroke, and sudden cardiac death, independent of traditional risk factors. According to American Heart Association guidelines, hs-CRP levels <1.0 mg/L indicate low cardiovascular risk, 1.0–3.0 mg/L suggest moderate risk, and >3.0 mg/L correspond to high risk. In AMI, hs-CRP levels typically rise within 24–48 hours, peaking around 72 hours, and are associated with infarct size, the extent of myocardial injury, and short- and long-term clinical outcomes [1, 3, 6, 7, 8].  In patients with diabetes mellitus—a population already characterised by chronic systemic inflammation—hs-CRP levels are often elevated at baseline. This inflammatory burden may contribute to a more severe post-AMI course and worse prognosis compared to non-diabetic individuals. Consequently, hs-CRP serves as an important inflammatory biomarker that adds prognostic value in risk stratification, particularly when integrated with clinical scoring systems in both diabetic and non-diabetic populations.

Pathophysiology of AMI and Inflammation

AMI results from a sudden reduction or complete cessation of coronary blood flow, most commonly due to the rupture or erosion of a vulnerable atherosclerotic plaque followed by thrombus formation. The pathophysiological process underlying AMI is deeply intertwined with inflammation, both as a precipitating factor and as a consequence of myocardial injury. The rupture of a plaque is often precipitated by inflammatory processes that weaken the fibrous cap and promote thrombotic activity. Once the plaque ruptures, exposure of subendothelial components triggers platelet adhesion, activation, and aggregation, as well as the activation of the coagulation cascade, resulting in the formation of an occlusive thrombus [10, 16]. As a result of ischaemia, myocardial cells undergo irreversible injury, releasing molecules that activate innate immune receptors that triggers the release of pro-inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumour necrosis factor-alpha (TNF-α), which amplify the inflammatory response. However, an excessive or prolonged inflammatory response can impair healing, promote adverse cardiac remodelling, and increase the risk of complications such as heart failure [17]. hs-CRP, produced by hepatocytes in response to IL-6, is a well-established marker of systemic inflammation. Its levels rise within hours of AMI onset, peaking around 48–72 hours, and correlate with infarct size and overall inflammatory burden. Elevated hs-CRP levels have been associated with increased risks of recurrent ischemic events, heart failure, arrhythmias, and mortality, underscoring the prognostic relevance of inflammation in AMI [4,8,9,17]. In patients with DM, chronic low-grade inflammation further exacerbates the atherosclerotic process and heightens the inflammatory response post-AMI, often leading to poorer outcomes. As such, understanding the inflammatory mechanisms underlying AMI provides valuable insight into disease progression, risk stratification, and potential therapeutic targets [1,2].

hs-CRP: Biomarker for cardiovascular risk

hs-CRP is a critical biomarker for assessing cardiovascular risk, particularly in AMI patients and those at risk for cardiovascular events. Unlike standard CRP, hs-CRP is more sensitive, detecting low-grade inflammation even at concentrations as low as 0.1 mg/L, making it ideal for early detection of cardiovascular risk. hs-CRP reflects chronic inflammation associated with cardiovascular diseases. It rises in response to interleukin-6, during plaque formation and instability in arteries. Levels above 3.0 mg/L are considered high risk, while levels below 1.0 mg/L indicate low risk [4,7,9]. Diabetes mellitus is a multifactorial metabolic disease and growing evidence shows that it is characterized by a state of sub-clinical inflammation [14], as reflected by chronic high levels of hs-CRP. In AMI, patients with DM show a more severe inflammatory condition than those without DM and this, in part, explains their higher short-term and long-term mortality risk. In diabetic patients, hs-CRP levels are often elevated due to chronic low-grade inflammation, worsening cardiovascular prognosis. This elevation increases the risk of complications post-AMI, including heart failure, arrhythmias, and recurrent myocardial events. Hs-CRP has also proven to be an independent risk factor for cardiovascular disease, even in the absence of other traditional risk factors. It is incorporated into risk scoring systems, such as the Framingham Risk Score, to enhance risk prediction. Additionally, hs-CRP can guide therapy, such as the use of statins, which lower hs-CRP and reduce cardiovascular events [10,11].

Prognostic Impact of hs-CRP in AMI

hs-CRP has increasingly been recognised as a powerful prognostic marker in patients with AMI. Elevated hs-CRP levels have been consistently linked to adverse cardiovascular outcomes in AMI patients [13]. Several studies demonstrate that hs-CRP levels are predictive of both short- and long-term outcomes following AMI. For instance, in STEMI patients, higher hs-CRP levels at admission are associated with larger infarct size, greater myocardial damage, and a higher risk of complications such as heart failure and arrhythmias. Studies show that hs-CRP is an independent predictor of mortality and major adverse cardiovascular events (MACE), even when adjusted for other traditional risk factors such as age, hypertension, and diabetes mellitus. In patients with diabetes mellitus, hs-CRP levels are often elevated, reflecting the chronic low-grade inflammation that accompanies diabetes. This elevation further exacerbates the risk of adverse outcomes following AMI. Higher hs-CRP in diabetics is associated with increased risk implying that its levels could be useful in distinguishing those with a higher likelihood of poor prognosis. Incorporating hs-CRP into routine clinical practice could improve the identification of high-risk AMI patients, leading to more tailored treatment strategies and better patient outcomes [15,17].

The Impact of DM on hs-CRP and Cardiovascular Outcomes in AMI

DM significantly influences the relationship between hs-CRP levels and cardiovascular outcomes in patients with AMI. Diabetic patients tend to have higher baseline levels of hs-CRP due to chronic low-grade inflammation, which exacerbates the inflammatory response following AMI. As mentioned, elevated hs-CRP in these patients is associated with more severe CAD, larger infarct sizes, and worse clinical outcomes, including increased risk of mortality, heart failure, and recurrent cardiovascular events [5, 11]. In addition, studies have shown that diabetes enhances the predictive power of hs-CRP for adverse outcomes in AMI. Diabetic patients with elevated hs-CRP levels are at a significantly higher risk of major adverse cardiovascular events (MACE) compared to non-diabetic patients. These findings highlight the critical role of hs-CRP as a marker of inflammation and its utility in risk stratification when compared to other standardized tools such as TIMI or GRACE, particularly in diabetic AMI patients who may benefit from continuous monitoring and therapeutic strategies [17, 19].

Clinical Applications of hs-CRP in Risk Stratification and Management

hs-CRP plays a significant clinical role in the risk stratification and management of patients with AMI. Elevated hs-CRP levels shortly after AMI are associated with adverse outcomes such as heart failure, arrhythmias, larger infarct size, and increased short- and long-term mortality. These associations underline its value as a prognostic biomarker, independent of traditional risk scores like GRACE and TIMI [17, 20]. Incorporating hs-CRP into clinical assessment can help identify high-risk patients who may benefit from closer monitoring, intensified therapy, or early intervention. For instance, patients with high hs-CRP levels post-AMI show better outcomes when treated with high-intensity statins, highlighting the role of inflammation modulation in secondary prevention [2, 9]. Furthermore, in diabetic AMI patients—who typically present with higher baseline hs-CRP—this marker enhances prognostic accuracy and supports more tailored therapeutic strategies. Thus, hs-CRP is not just a passive biomarker but an active tool in guiding clinical decisions, improving personalizsed management plans, and potentially enhancing cardiovascular outcomes in both diabetic and non-diabetic AMI patients.

LIMITATIONS AND FUTURE DIRECTIONS

Despite consistent evidence supporting the prognostic significance of hs-CRP in patients with AMI, several limitations are evident across current literature. Many of the existing studies are observational in nature, limiting the ability to infer causality between elevated hs-CRP levels and adverse cardiovascular outcomes. Variability in study populations, sample sizes, and follow-up durations also affects the generalisability of findings. Furthermore, while elevated hs-CRP is associated with poor outcomes, it remains a nonspecific marker of inflammation and can be influenced by comorbid conditions such as infections, autoimmune disorders, and malignancies — factors that may confound its prognostic utility in AMI. Another key limitation is the lack of standardised timing and thresholds for hs-CRP measurement across studies, which complicates comparison and interpretation of results. Additionally, few studies have specifically focused on stratified analyses based on diabetic status, limiting our understanding of the differential prognostic value of hs-CRP in diabetic versus non-diabetic patients. Future research should aim to establish standardised protocols for hs-CRP assessment in the setting of AMI and determine optimal cutoff values for risk stratification. Large-scale, prospective, multicentre trials are needed to clarify whether hs-CRP-guided treatment strategies, particularly anti-inflammatory therapies, can result in improved clinical outcomes. Moreover, given the higher baseline inflammatory state in patients with diabetes mellitus, more focused investigations are warranted to explore whether intensified therapeutic approaches based on hs-CRP levels could improve prognosis in this high-risk subgroup. Integrating hs-CRP with other emerging biomarkers and imaging modalities may also enhance its predictive accuracy and contribute to more precise, personalised risk assessment in AMI patients.

CONCLUSION

The collective evidence from current literature underscores the prognostic relevance of high-sensitivity C-reactive protein (hs-CRP) in patients with acute myocardial infarction (AMI). Elevated hs-CRP levels have been consistently associated with greater infarct size, increased incidence of arrhythmias, development of heart failure, and higher mortality rates. These associations appear particularly pronounced in patients with diabetes mellitus, reflecting the interplay between systemic inflammation and adverse cardiovascular outcomes. Despite its nonspecific nature, hs-CRP provides incremental prognostic information beyond traditional risk scores and remains a widely accessible biomarker. However, heterogeneity in study designs, patient populations, and hs-CRP measurement protocols limits the generalisability of findings. Moving forward, standardised assessment strategies and further exploration of hs-CRP-guided therapeutic interventions—especially in high-risk subgroups—are necessary. Incorporating hs-CRP into comprehensive risk stratification models may enhance the precision of post-AMI management and improve long-term clinical outcomes.

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