Repeat C-Reactive Protein Measurements May Refine Cardiovascular Risk Stratification

An analysis featured at the 75th Annual Scientific Session of the American College of Cardiology, in New Orleans, revealed an association between persistently elevated C-reactive protein (CRP) levels and incident first-time myocardial infarction, highlighting the importance of repeating measurements of inflammatory markers for cardiovascular risk stratification.  

CRP, an inflammatory marker synthesized in the liver in response to cytokines and NLRP3 inflammasome activity, is a predictor of cardiovascular events. Individuals with chronic inflammation or disease-related inflammatory states that persist over time have an elevated risk of cardiovascular disease and may benefit from targeted therapies and prevention. Nevertheless, because CRP levels fluctuate over time, this biomarker is considered to have limited clinical utility for risk stratification. 

“There is a known causal relationship between inflammation and risk for cardiovascular disease, presenting author Daniel Weiner, MD, PhD, a resident at Massachusetts General Hospital in Boston, said in an interview. “Some people have chronic underlying inflammation from either an identifiable condition, like an autoimmune disease, or from subclinical [processes]. But for some people it is more dynamic, like [acute] illness. The current guidelines mention inflammation as a risk modifier for cardiovascular disease, as a one-off measure, but it needs to have some sort of durability over time to properly reflect an inflammatory state that leads to increased cardiovascular risk.”  

Weiner and colleagues used UK Biobank, a large-scale biomedical database that contains data from half a million volunteers, to identify individuals who had two CRP measurements over time. The individuals identified for the analysis had an average age of 58 years and included nearly equal proportions of men and women. CRP values at baseline and on repeat assessment over a 4-year interval were collected from nearly 15,000 individuals without a diagnosed underlying inflammatory condition. CRP elevation was defined as values equal to or higher than 2 mg/L. 

The researchers then looked at the relationship between the stability of inflammatory markers over time and incident myocardial infarction. Among the 10,566 individuals with non-elevated CRP levels at baseline, 83% had non-elevated CRP levels when the test was repeated. Sixty-two percent of the 4,394 individuals with elevated CRP levels at baseline also had elevated levels when the biomarker was assessed a second time. The analysis showed that a single elevated CRP measurement was not significantly associated with incident myocardial infarction, whether the elevated CRP levels were detected at baseline or when tests were repeated. On the other hand, elevated CRP levels at both assessment points signaled a higher risk of incident myocardial infarction compared to non-elevation or inconsistent elevation. 

“We saw that people who had durable inflammation, high at baseline and high at repeat [assessment], had the highest incidence of myocardial infarction, whereas people who had either a high-low or a low-high pattern had an intermediate risk that was not statistically significant,” Weiner said. “Perhaps there is no relationship or perhaps it is underpowered, but they certainly [have] a different [risk level] than people who had high measurements [both times]. This suggests that, if we are using inflammation to guide risk stratification, it would be prudent to look at inflammation over time through repeat measurements as opposed to just a one-off metric.”  

The author noted that cost and logistical barriers may be preventing the integration of standard CRP measurements into clinical guidelines. However, repeat measurements of inflammatory markers for prevention purposes may be less burdensome than managing patients with coronary artery disease, Weiner added. 

Approximately 3% of the studied group (426 individuals) sustained a first-time myocardial infarction over a median follow-up period of 11.5 years after the second CRP measurement. However, not all people who sustained a myocardial infarction had elevated CRP levels at both assessments. These results suggest that, while consistently elevated levels of CRP over time increase risk for cardiovascular disease, this is just one of many risk factors that may contribute to adverse cardiovascular events.