C-reactive protein and cardiovascular risk among women with no standard modifiable risk factors: evaluating the ‘SMuRF-less but inflamed’

Abstract Background and Aims Interventions in preventive cardiology traditionally focus on four standard modifiable cardiovascular risk factors (SMuRFs): hypertension, dyslipidaemia, diabetes mellitus, and smoking. Yet, a substantial proportion of incident cardiovascular events accrues for individuals with none of these factors, particularly among women for whom cardiovascular disease remains under-detected and under-treated. The utility of the inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) was evaluated to detect cardiovascular risk in SMuRF-less women participating in the prospective NIH-funded Women’s Health Study. Methods High-sensitivity C-reactive protein was measured at baseline among 12 530 initially healthy American women with no standard modifiable risk factors who were followed over 30 years for first major adverse cardiovascular events (myocardial infarction, coronary revascularization, ischaemic stroke, or cardiovascular death). Hazard ratios (HRs) and 95% confidence intervals (95% CI) for incident coronary heart disease (CHD), ischaemic stroke, and total cardiovascular events were calculated across quintiles of hsCRP, along with 30-year cumulative incidence curves. Hazard ratios were also computed according to common clinical thresholds of hsCRP, according to standard deviation change in hsCRP, and as a continuous variable in penalized spline regression models. Results During 30-year follow-up, 973 first major cardiovascular events accrued. Median baseline hsCRP was significantly higher among SMuRF-less women who subsequently suffered a cardiovascular event when compared with those who did not (median hsCRP 2.22 vs 1.50 mg/L, P < .0001). In age-adjusted analyses, the HRs for the primary endpoint of incident CHD from lowest (referent) to highest levels of hsCRP at study entry were 1.0 (referent), 1.24, 1.41, 1.57, and 2.23 (P-trend < .0001) such that CHD risk over 30 years increased 21% for each increasing quintile of hsCRP (age-adjusted HR 1.21, 95% CI 1.13–1.29, P < .0001). Corresponding HRs for the top vs bottom quintile of hsCRP were 1.69 (95% CI 1.16–2.47) for ischaemic stroke and 1.74 (95% CI 1.42–2.14) for total cardiovascular disease events. Using common clinical hsCRP thresholds, SMuRF-less women with hsCRP > 3 mg/L had a 77% higher risk of CHD events, a 39% higher risk of ischaemic stroke events, and a 52% higher risk of total cardiovascular disease events when compared with those with hsCRP < 1 mg/L. Spline analyses demonstrated linear association with risk across the spectrum of hsCRP values. Hazards were moderately attenuated after additional adjustment for body mass index and estimated glomerular filtration rate [covariate-adjusted CHD HR 1.86 (95% CI 1.35–2.58, P = .0002) for comparison of the top vs bottom quintile of hsCRP and 1.52 (95% CI 1.20–1.92, P = .0006) for comparison of those with hsCRP > 3 mg/L to those < 1 mg/L]. Conclusions Over a 30-year horizon, cardiovascular events commonly occur among ‘SMuRF-less but inflamed’ women who are otherwise missed by current screening algorithms, a clinically important observation given recent trial data demonstrating that statin therapy reduces risk by 38% among such individuals.