Highlight
1. Potent Risk Prediction in the General Population
Large-scale data from the UK Biobank confirm that hsCRP levels >3 mg/L are associated with a 34% increased risk of major adverse cardiovascular events (MACE) and over 50% increased risk of cardiovascular and all-cause mortality, outperforming several conventional risk factors.
2. The SMuRF-less but Inflamed Paradox
Women without standard modifiable risk factors (SMuRFs)—such as hypertension, diabetes, or smoking—still face a 77% higher risk of coronary heart disease over 30 years if their hsCRP exceeds 3 mg/L, highlighting a significant gap in current screening algorithms.
3. Improved Clinical Reclassification
Integrating hsCRP into established risk models like SCORE2 provides a total net reclassification improvement of 14.1% for MACE, suggesting its routine use could significantly refine primary prevention strategies.
4. Identifiable Drivers and Barriers
While obesity, smoking, and female sex are primary drivers of elevated hsCRP, clinical adoption of testing is hindered by perceived lack of evidence regarding outcome improvements and practical issues like insurance coverage.
Background: The Residual Inflammatory Risk
For decades, cardiovascular risk assessment has focused heavily on the ‘big four’ modifiable risk factors: hypertension, dyslipidemia, diabetes, and smoking. However, a significant proportion of cardiovascular events occurs in individuals who do not meet the criteria for these standard risk factors. This has led to the emergence of the ‘inflammatory hypothesis’ of atherothrombosis, which posits that systemic inflammation plays a central role in the initiation and progression of atherosclerotic cardiovascular disease (ASCVD).
High-sensitivity C-reactive protein (hsCRP) has emerged as the most robustly studied biomarker of this systemic inflammation. Despite extensive research, its role as a routine clinical tool remains debated. Clinicians often struggle with the ‘residual inflammatory risk’—the risk that remains even after aggressive lipid-lowering and blood pressure management. Understanding the clinical relevance of hsCRP across diverse populations, from healthy individuals to those with established ASCVD, is essential for refining personalized prevention strategies.
Study Design and Methodological Approaches
The evidence presented here spans four distinct yet complementary studies. The first, a massive population-based study utilizing the UK Biobank, analyzed 448,653 participants without known ASCVD to assess the long-term predictive value of hsCRP for MACE and mortality. A subset of nearly 16,000 participants underwent repeat testing after 4.4 years to evaluate the biomarker’s stability.
The second study, a cross-sectional analysis of both the UK Biobank (n=23,045) and the US NHANES (n=3,415) cohorts, focused on individuals with existing ASCVD. It sought to identify specific clinical factors—such as BMI, smoking status, and lipid levels—associated with elevated hsCRP (2-10 mg/L).
The third study, derived from the prospective Women’s Health Study, followed 12,530 ‘SMuRF-less’ American women (those without hypertension, diabetes, dyslipidemia, or smoking history) over a 30-year horizon. This study specifically evaluated how baseline hsCRP levels predict long-term incident coronary heart disease (CHD) and stroke.
Finally, a survey-based study of US cardiologists and nephrologists (June–August 2023) provided insights into the real-world perceptions, drivers, and barriers regarding hsCRP testing in clinical practice.
Key Findings: A Deep Dive into CRP and Cardiovascular Outcomes
Predictive Power in Primary Prevention
In the general population analysis of the UK Biobank, hsCRP demonstrated remarkable stability over time. The median hsCRP was 1.32 mg/L, but those with levels exceeding 3 mg/L faced significantly higher hazards. Specifically, the risk of MACE was 34% higher (HR 1.34), while the risks for cardiovascular death and all-cause death were elevated by 61% and 54%, respectively, compared to those with hsCRP <1 mg/L.
Crucially, the predictive performance of hsCRP ranked above several conventional risk factors. When integrated into the SCORE2 risk model, hsCRP improved the net reclassification by 14.1%. This suggests that adding hsCRP to standard models helps clinicians more accurately identify 'high-risk' patients who might otherwise be classified as 'intermediate risk.'
Determinants of Inflammation in Established ASCVD
In patients who already have ASCVD, certain factors consistently correlate with higher inflammatory burdens. Multivariable logistic regression across both UK and US cohorts identified obesity as the strongest predictor (UK Biobank OR: 3.48; NHANES OR: 4.11). Other significant factors included:
- Overweight status (OR 1.56–2.26)
- Current smoking (OR 1.96–2.47)
- Female sex (OR 1.69)
- Elevated LDL-C and triglycerides
Conversely, the use of statins was associated with significantly lower odds of elevated hsCRP (UK Biobank OR 0.69; NHANES OR 0.54), reinforcing the ‘pleiotropic’ anti-inflammatory effects of HMG-CoA reductase inhibitors.
The ‘SMuRF-less’ Population: A Hidden Risk Group
Perhaps the most striking findings come from the Women’s Health Study. Among women with zero standard modifiable risk factors, those in the highest quintile of hsCRP had a 77% higher risk of CHD events compared to those in the lowest quintile. Over a 30-year period, the risk of ischemic stroke was 69% higher and total CVD events were 74% higher for those in the top quintile. Even after adjusting for BMI and kidney function, the association remained robust (HR 1.86 for CHD). This ‘SMuRF-less but inflamed’ phenotype identifies a group of women who are currently missed by traditional screening but who may benefit significantly from early intervention.
Clinical Perceptions and Implementation Gaps
Despite the strong epidemiological data, a survey of US specialists revealed significant inertia. Approximately 50% of surveyed clinicians cited a lack of evidence showing that addressing systemic inflammation actually improves patient outcomes as a reason for not testing. Furthermore, 33% questioned the efficacy of the test itself. Cost, insurance coverage, and the perception that hsCRP results would not change management were cited as major barriers. Interestingly, even when testing was performed, the average post-test hsCRP level remained above the 2 mg/L threshold, suggesting that current interventions may not be sufficiently aggressive in reducing inflammatory risk.
Expert Commentary
The data collectively reinforce that inflammation is not merely a bystander in cardiovascular disease but a central player. The stability of hsCRP over 4.4 years in the UK Biobank study is particularly important, as it suggests that a single measurement can provide a reliable long-term risk signal, much like LDL cholesterol.
From a clinical perspective, the ‘SMuRF-less’ data are a call to action. We have long known that women’s cardiovascular risk is often underestimated. By incorporating hsCRP, we can unmask high-risk individuals who appear ‘healthy’ by traditional metrics. The fact that statin therapy has been shown to reduce risk by 38% in such individuals (as noted in the JUPITER trial context) provides a clear therapeutic pathway.
However, the survey data highlight a disconnect between clinical evidence and practice. The ‘lack of evidence’ cited by clinicians likely refers to a perceived lack of large-scale randomized controlled trials (RCTs) specifically targeting inflammation to improve outcomes. While the CANTOS (canakinumab) and COLCOT (colchicine) trials have provided this evidence, it seems these findings have not yet fully permeated general clinical practice or influenced payer policies. Addressing the ‘residual inflammatory risk’ requires not just better biomarkers, but a shift in the treatment paradigm to include anti-inflammatory therapies alongside lipid-lowering agents.
Conclusion
High-sensitivity CRP is a clinically validated, stable, and potent predictor of cardiovascular events across the spectrum of primary and secondary prevention. It is particularly valuable in identifying risk in populations currently underserved by standard algorithms, such as women without traditional risk factors. While its integration into models like SCORE2 offers superior risk reclassification, clinical adoption remains hampered by institutional and perceptual barriers. Moving forward, targeted testing in patients with identifiable risk drivers (like obesity and smoking) and the adoption of emerging anti-inflammatory protocols will be essential to further reduce the global burden of cardiovascular disease.
References
1. Kurt B, et al. C-reactive protein and cardiovascular risk in the general population. Eur Heart J. 2025; ehaf937.
2. Ray KK, et al. Factors Associated with Elevated High-Sensitivity C-Reactive Protein Levels in Individuals with Atherosclerotic Cardiovascular Disease in the US and the UK. Eur J Prev Cardiol. 2025; zwaf609.
3. Ridker PM, et al. C-reactive protein and cardiovascular risk among women with no standard modifiable risk factors: evaluating the ‘SMuRF-less but inflamed’. Eur Heart J. 2025; ehaf658.
4. Lv L, et al. Perceptions of high-sensitivity C-reactive protein testing (hsCRP) in atherosclerotic cardiovascular disease: a US survey on cardiologists and nephrologists. Future Cardiol. 2025; 21(9):701-710.
