Inactivity and Unhealthy Diets Drive Cardiovascular Risk Through Inflammatory and Microbiome Alterations

Abstract

This paper presents evidence investigating the causal pathways through which physical inactivity and unhealthy eating contribute to heart disease onset, integrating epidemiological, biological, and socio-contextual evidence. Our review reveals that both ultra-processed food consumption and prolonged sedentary behavior independently elevate cardiovascular risk, with pooled meta-analyses demonstrating a 23% higher coronary heart disease risk for the highest versus lowest ultra-processed food intake. Furthermore, combined unhealthy profiles of poor diet and inactivity produce additive interactions for cardiovascular risk factors including LDL cholesterol, hypertension, and type 2 diabetes. Biological mediation analyses strongly implicate systemic inflammation and gut microbiome alterations as key mechanistic pathways; for instance, higher ultra-processed food intake was associated with elevated interleukin-18 and resistin levels independent of traditional metabolic risk factors, while the Framingham Heart Study showed that microbial diversity decreases with higher ten-year cardiovascular disease risk. Importantly, genetic susceptibility is partially modifiable by lifestyle-UK Biobank data indicate that individuals at the 90th percentile of genetic risk who engaged in higher physical activity had a 39–59% lower hazard of coronary artery disease compared to sedentary counterparts with identical genetic risk. Socio-environmental determinants, particularly socioeconomic status and built environment characteristics, significantly confound and moderate these causal relationships. This work unifies independent and synergistic lifestyle effects, biological mediation through inflammation and microbiome, and socio-contextual moderation, thereby informing targeted prevention strategies for reducing the global burden of heart disease.