After years of research on the inflammatory hypothesis, some say it’s time to integrate the concept into daily practice.
MADRID, Spain—Women who lack standard modifiable cardiovascular risk factors (SMuRFs) but have elevated levels of high-sensitivity C-reactive protein (hs-CRP) are at increased risk of experiencing cardiovascular events over the next three decades, new data from the Women’s Health Study suggest.
The risk of coronary heart disease, ischemic stroke, and total CV events rose progressively across quintiles of the biomarker, Paul Ridker, MD (Brigham and Women’s Hospital, Boston, MA), reported today at the European Society of Cardiology (ESC) Congress 2025.
“What I’d like to do today is create this new thing for all of us to think about clinically: SMuRFless but inflamed,” Ridker said to kick off his presentation. This concept has gained traction in research on secondary prevention, he told attendees of the Late-Breaking Clinical Science session, but it’s also appealing for primary prevention.
SMuRFless patients “still have a lot of heart attacks and a lot of strokes” in comparison to people burdened by traditional risk factors, he added, and account for around half the global burden of CVD. Exactly why isn’t known, though it could be “either because we’re not recognizing them or because the biology itself might be a little bit different.”
The question is whether inflammation might explain some of that added risk and—on the backdrop of data from the JUPITER trial suggesting statins can benefit both male and female patients with high hs-CRP but without traditional risk factors—be a useful screening tool. “We hypothesize that a single baseline measure of CRP obtained in midlife would probably predict future cardiovascular risk in apparently healthy SMuRFless women,” said Ridker.
Importantly, “our guidelines need to recognize that until we tell physicians inflammation matters, they will not measure it. And [if] they don’t measure it, they will not treat it,” he stressed.
The results were published simultaneously in the European Heart Journal.
Natalie Arnold, MD (University Medical Center Hamburg-Eppendorf, Germany), and Wolfgang Koenig, MD (Technical University of Munich, Germany), in an accompanying editorial, agree SMuRFless patients aren’t uncommon, with up to 25% of first CV events occurring in the absence of these common risk factors. Moreover, the lifetime risk of CV events for these individuals is around 13% in women and 21% in men.
“How many practicing cardiologists have faced the bitter reality of a woman in her early fifties who has never smoked, is of normal weight, and has ideal blood pressure, low density lipoprotein cholesterol, and fasting glucose—but nonetheless [is] presenting to the emergency department with an acute myocardial infarction?” they ask.
This gap, Arnold and Koenig say, “underscores the urgent need for additional tools that can detect low-risk individuals who are, biologically, not low risk at all.”
Linear Relationships Seen
Ridker and colleagues analyzed data for 12,530 women (median age 53.2 years) without prior CVD and without SMuRFs—specifically hypertension, dyslipidemia, diabetes mellitus, and smoking—who had hs-CRP measured at baseline as part of the National Institutes of Health-funded Women’s Health Study. Among them, 973 had first major cardiovascular events (MI, coronary revascularization, ischemic stroke, or CV death) over the 30-year follow-up.
Women who experienced events had higher median hs-CRP levels (2.22 vs 1.50 mg/L, P < 0.0001). Adjusted for age, the risk of coronary heart disease (CHD) was doubled for individuals with the highest (≥ 4.23 mg/L) versus lowest quintiles (< 0.49 mg/L) of hs-CRP (HR 2.23; 95% CI 1.65-3.03). Similarly, the risks in the top versus bottom quintiles were elevated for ischemic stroke (HR 1.69; 95% CI 1.16-2.47) and total CVD events (HR 1.74; 95% CI 1.42-2.14).
Women with hs-CRP > 3 mg/L had risks of CHD, ischemic stroke, and total CVD events that were 77%, 39%, and 52% higher, respectively, than those with hs-CRP < 1 mg/L. The associations were linear across the spectrum of hs-CRP values but were “moderately attenuated” after adjustment for body mass index and estimated glomerular filtration rate.
Following the presentation, ESC attendees seemed curious about practicalities. One raised the question of when is the best time to measure hs-CRP.
“If I ask the audience, at what age should we measure LDL cholesterol or at what age we measure blood pressure, we would all say, ‘What a silly question, we should do it to everybody on a regular basis,’” Ridker replied, adding that inflammation should be thought of as an integral part of CVD. “We know the CRP levels are already increased in teenagers [and] young adults. We should be doing this universally.” Moreover, hs-CRP is low cost to measure and readily accessible in practice, he noted, and statins are quite affordable.
Another audience member asked whether the evolution in thresholds for things like cholesterol and blood pressure in terms of who should get treated, and to which target, impacts interpretation of SMuRFs.
Reassuringly, this analysis didn’t identify particular cutoffs for what’s clinically meaningful, said Ridker. “We can [debate over] what a true SMuRF is or isn’t, but it’s not going to change the outcome very much.”
The editorialists similarly advise that any strategy for identifying—and addressing—the SMuRFless phenotype in practice must be “simple and actionable.”
“A once-in-adulthood hs-CRP check, repeated to confirm persistence if elevated and interpreted in the absence of acute illness, could identify a SMuRFless subgroup whose absolute risk over the next decade or two might be nonnegligible,” they suggest. “This is not a call for universal inflammation screening at every visit, rather a reminder that hs-CRP is a population-level risk indicator that, used thoughtfully, can improve calibration at the bedside.”