Cardiovascular disease (CVD) is responsible for almost a third of deaths in women globally — more than all forms of cancer combined. It is the leading cause of maternal mortality, and yet, women make up less than 40% of participants in clinical trials, limiting timely diagnosis and, often, initiation of lifesaving treatments.

Part of the challenge lies with identifying otherwise healthy individuals — especially women — who lack standard modifiable cardiovascular risk factors (SMuRFs; such as hypertension, dyslipidemia, diabetes, and smoking) but still experience serious CVD events such as acute myocardial infarction (AMI).

Data have suggested that SMuRF-less women experience as much as a threefold higher AMI mortality rate than men with at least 1 modifiable risk factor. Though the underlying reason has evaded researchers for decades, study findings presented at the European Society of Cardiology Conference and simultaneously published in The European Heart Journal demonstrate that highly sensitive C-reactive protein (hsCRP) might hold the key.

“We published a paper last year showing that randomly measured hsCRP predicted with greater fidelity the long-term risk for a first major cardiovascular event (compared with low-density lipoprotein cholesterol (LDL-C) and lipoprotein(a)),” said lead study author Paul Ridker, MD, MPH, professor of medicine at Harvard Medical School and director of Cardiovascular Disease Prevention Center at the Massachusetts General Hospital in Boston.

For the current paper, researchers looked at the blood samples from 12,530 initially healthy American women (enrolled in the Women’s Health Study and followed for 30 years) who, by definition, had none of the major risk factors, Ridker said. “Women who had an hsCRP greater than 3 mg/L, which is the threshold for increased risk in the general population, had a 77% increased risk for coronary heart disease, and this was equally true for cardiovascular events (52% increased risk) and stroke (39% increased risk).”

These risks remained after adjustment for BMI and renal function.

“This is one of [the] several recent papers that really have been a paradigm shift for prevention that we really need to be thinking about inflammation not only as an independent risk factor but [also] potentially as a target of therapy in and of itself,” said Erin Donnelly Michos, MD, professor of medicine at Johns Hopkins University School of Medicine in Baltimore, director of the Women’s Cardiovascular Health Research, and associate director of preventive cardiology at Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, who was not involved in the study.

From Research to Practice

An accompanying reanalysis of the primary prevention JUPITER trial, in which a total of 8728 men and women with no discernable modifiable risk factors but hsCRP levels > 2 mg/L were randomly assigned to rosuvastatin 20 mg daily or placebo, underscored the value of statin therapy for what Ridker coined the “SMuRF-less but inflamed” population. Participants randomly assigned to the statin experienced a reduction in major adverse CVD events by 38% (hazard ratio, 0.62; 95% CI, 0.45-0.85).

The takeaway?

In addition to diet, exercise, and other lifestyle recommendations, physicians might want to consider starting SMuRF-less but inflamed patients on a statin earlier before the disease is established, said Ridker.

“CRP is an early risk marker and is analogous to some of the other risk enhancers we think are important in women, such as pregnancy complications, rheumatologic disease, and other factors of that nature,” said Nisha Parikh, MD, MPH, associate professor of cardiology at Hofstra University in Hempstead and system director of the Women’s Heart Health Program at Northwell Health in New Hyde Park, both in New York.

“Most of the guidelines would suggest that it’s reasonable to measure CRP in a patient when we are trying to further refine their risk that we’ve measured via standard risk scores,” she said. “So in that sense, it’s an actionable item.”

Parikh recalled a recent patient with a rheumatologic condition but no other risk factors who she was seeing for a preventive visit.

“Not surprisingly, her CRP was very high — in the double digits — as she was having an active flare of her rheumatologic condition. I suggested a statin for her, just based on the rheumatologic condition and the CRP, even in the absence of other classic, established CVD risk factors,” said Parikh.

Nieca Goldberg, MD, cardiologist and clinical associate professor of medicine at NYU Grossman School of Medicine in New York City, said that she’s seen a number of SMuRF-less women during her years of practice.

“Very early in my career when I started focusing my practice on women and heart disease, I had a patient who needed a stent. I remember being in the room with her and her husband and he saying ‘I smoke cigars. I eat steak. She exercises all the time and does everything right.’”

“I think that it’s important when it’s not clear why patients had heart attacks without traditional risk factors that you have to look elsewhere,” she said. “We often look at inflammation as something that can promote atherosclerosis or buildup of cholesterol and other inflammatory proteins in the arteries. HsCRP is a blood test where we can test for that.”

The study was funded by the National Heart, Lung, and Blood Institute. Ridker reported receiving independent grant support and/or consultant fees from Novo Nordisk, Novartis, Amarin, Pfizer, Espirion, and others. Michos reported being part of consulting/advisory boards for the following companies: Arrowhead Pharmaceuticals, Bayer, Boehringer Ingelheim, Edwards Lifesciences, Ionis, Eli Lilly and Company, Merck, NewAmsterdam Pharma, Novartis, Novo Nordisk, and Pfizer. Parikh and Goldberg reported having no relevant financial relationships. 

Liz Scherer is an independent health journalist and frequently reports on Canadian and Global health news.