Synergistic effects of circulating monocyte accumulation and cardiometabolic abnormalities on all-cause mortality:...

Chronic monocytosis and enhanced hematopoietic activity are increasingly recognized as core features of immune-metabolic dysregulation and accelerated biological ageing. However, conventional cardiometabolic risk assessment fails to capture these early immunological alterations, leaving substantial residual risk unaddressed. Within the predictive, preventive, and personalised medicine (PPPM/3PM) framework, longitudinal profiling of monocyte accumulation may provide a sensitive biomarker for early risk prediction and an actionable target for upstream prevention. This study aimed to determine whether chronic monocytosis predicts all-cause mortality and whether it interacts with cardiometabolic abnormalities to define high-risk immunometabolic phenotypes that may guide personalised prevention strategies.

We hypothesised that chronic monocyte accumulation synergises with cardiometabolic abnormalities to form a high-risk immunometabolic phenotype that enables early prediction, targeted prevention, and personalised management of mortality risk. Leveraging data from a real-life, prospective cohort in Northern China, chronic monocytosis was quantified as cumulative monocyte exposure (CumMON) over a six-year period. Multivariable time-to-event models, including interaction analyses on both multiplicative and additive scales, were applied to 43,681 Han Chinese adults to evaluate the independent and joint associations of CumMON and cardiometabolic risk profiles with all-cause mortality. Incremental predictive performance was quantified using changes in C-index and reclassification metrics.

During a median follow-up of 7.76 years, 2,810 deaths occurred. Each 1-SD increase in CumMON was associated with a 15% higher mortality risk (HR: 1.15, 95% CI 1.11-1.20), independent of conventional risk factors. Adding CumMON to multivariable models improved prediction (net reclassification improvement: 12.05%, P < 0.001). Stronger associations were observed among individuals with diabetes, hypertension, renal dysfunction, dyslipidemia, or systemic inflammation but not those with pre-existing cardiovascular disease or cancer. Supra-additive interactions with diabetes (relative excess risk due to interaction = 0.26 [0.04-0.48]) and hypertension (0.35 [0.12-0.57]) indicated synergistic effects on excess mortality.

Among Chinese adults, chronic monocytosis was independently associated with increased mortality risk and amplification of cardiometabolic vulnerability, indicating a high-risk immunometabolic state. Within the 3PM paradigm, longitudinal tracing of circulating monocytes may offer a practical approach for early identification of health-to-disease transition. Targeted prevention focusing on modifiable immunometabolic pathways may help mitigate excess risk, while monocyte-based profiling could inform personalized risk assessment and risk-adapted management. These findings promote a shift toward predictive, preventive, and personalised strategies aimed at to improving survival and promoting healthy ageing.

The online version contains supplementary material available at 10.1007/s13167-026-00439-6.