Atherosclerotic cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide [1]. Despite advances in lifestyle interventions and contemporary pharmaceutical strategies for cardiovascular health, there remains a need for approaches to identify the residual risk of future atherosclerotic events to refine preventive strategies.

There is a well-established relationship between low-grade systemic inflammation and the incidence of CVD [2,3]. Emerging evidence has also demonstrated that inflammation exacerbates cerebral atherogenesis and contributes to the future risk of stroke events [[4], [5], [6], [7]]. Recent randomized clinical trials have demonstrated that reducing inflammation could significantly lower the risk of future cardiovascular events [[8], [9], [10]]. High-sensitivity C-reactive protein (CRP) is a benchmark inflammatory biomarker for selecting individuals at high inflammatory risk in both primary and secondary prevention settings of CVD. However, CRP is likely a downstream product of the inflammation cascade and thus may not play a causal role in atherosclerotic ischemic events [3]. As multiple inflammatory processes are involved in atherosclerosis, CRP alone may not adequately reflect inflammatory levels. Recent studies using data from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort and Cardiovascular Inflammation Reduction Trial (CIRT) indicated that the correlation between CRP and interleukin-6, an upstream inflammatory biomarker of CVD, was only modest [11,12]. There were insignificant relationships between CRP and major adverse cardiovascular events after adjusting for interleukin-6 [12]. However, cytokines are not routinely tested in clinical practice, necessitating further investigations into more easily accessible biomarkers to provide complimentary assessment of the inflammatory risk in the general population, rather than relying on a standalone predictor.

Multiple immune cells participate in atherosclerotic plaque formation. Among them, monocytes play a crucial role in the context of injured vascular endothelium. Monocytes can infiltrate vascular walls to take up oxidized low-density lipoprotein in the form of macrophages and secrete various pro-inflammatory cytokines including interleukin-6, thereby contributing to the formation of atherosclerotic plaques [13,14]. High-density lipoprotein (HDL) is widely recognized as a protective factor against cardiovascular events through multiple anti-inflammatory mechanisms, such as reducing monocytosis and mitigating inflammatory effects and oxidative stress secondary to monocyte activation [15]. Recently, the monocyte to high-density lipoprotein ratio (MHR) calculated as the monocyte count divided by the HDL level has been proposed as a novel index of systemic inflammation for predicting future cardiovascular risk [16,17]. Previous studies have shown that MHR is associated with unfavorable outcomes in patients with myocardial infarction or stroke [[16], [17], [18]], whereas the relationships between MHR and incident myocardial infarction, stroke, and mortality have rarely been explored at the population level.

In the current analysis, using the UK Biobank study, a large-scale prospective population-based cohort across the United Kingdom, we investigated the associations of MHR with incident myocardial infarction, stroke, cardiovascular mortality, and all-cause mortality. In addition, we aimed to test the hypothesis that MHR may provide additional value in predicting the future risk of cardiovascular events and mortality among individuals with no history of cardiovascular or stroke events.