Coronary artery disease in the absence of standard modifiable risk factors (SMuRFs): the impact of sex

The identification and targeting of standard modifiable risk factors (SMuRFs) - hypertension, dyslipidaemia, diabetes, and smoking - have led to significant improvements in cardiovascular outcomes over the past decades. However, clinical algorithms that rely on these SMuRFs only provide part of the solution, with 14-25 % of myocardial infarction patients presenting without these risk factors, and these factors accounting for only 53-56 % of incident cardiovascular disease (CVD) events globally. These algorithms perform particularly poorly in women, with SMuRFless women who suffer myocardial infarction (MI) experiencing a nearly threefold higher risk of early mortality compared to men with at least one risk factor. As the decline in global cardiovascular mortality has slowed markedly for women over the past decade, there is a pressing need for new solutions that extend beyond population-level risk factor models. Advances in CT coronary angiography allow for the non-invasive detection of coronary atherosclerosis; the causal disease underlying MI. When combined with blood-based biomarkers, this holds promise for a shift towards precision preventative cardiology. To enable scalable and equitable implementation, coordinated global efforts are needed to couple biomarker discovery with implementation into clinical pathways capable of detecting subclinical CAD before events occur. Such strategies hold potential not only for more individualized treatment, but also for monitoring of disease activity and remission, and for accelerating the translation of novel therapeutics. This review outlines emerging innovations in risk stratification, diagnostics, clinical pathways and drug development, with an emphasis on the critical need to incorporate sex as a biological variable throughout.