DNAmTIMP1 as a Predictor of Cardiovascular Disease and Mortality: A Prospective Analysis from the NHANES

Background TIMP1(tissue inhibitor metalloproteinase 1 ) represents a tissue metalloprotease that modulates the degradation of the extracellular matrix by inhibiting the activity of matrix metalloproteinases. Furthermore, it has the capacity to activate signaling pathways that lead to an overproduction of collagen, thereby enhancing extracellular matrix synthesis through the interaction between surface CD63 and integrin beta1 on cardiac fibroblasts, which results in increased ventricular stiffness, fosters cardiac fibrosis, and ultimately contributes to a decline in relaxation performance. DNA methylation constitutes an epigenetic modification. Alterations in the methylation landscape considerably influence gene expression changes associated with cardiac architecture and functionality. Recently, an evaluation of TIMP1 based on DNA methylation, referred to as DNAmTIMP1, was utilized to assess TIMP1 tools. Our latest study revealed a strong link between DNAmTIMP1 and the likelihood of cardiovascular disease, along with continued mortality in individuals of middle and advanced age. Methods We established a comprehensive, population-representative cohort derived from the National Health and Nutrition Examination Survey conducted between 1999 and 2002, which encompasses data pertaining to DNA methylation predicted tissue inhibitor metalloproteinase 1 used to predict the time of death for GrimAge and GrimAge2,which is used to predict human mortality risk and the rate of biological aging as an epigenetic biomarker based on DNA methylation[16]. By applying logistic regression and Cox proportional hazards models, we methodically examined the associations between DNAmTIMP1 and cardiovascular disease (CVD) risk, along with mortality outcomes. Results The study group was made up of 2466 individuals, with cardiovascular disease (CVD) having a weighted prevalence of 18.9%. Significantly, each one-kilobase increase in DNAmTIMP1 was linked to a 54% increase in the likelihood of developing CVD [odds ratio (OR): 1.54, 95% confidence interval (CI): 1.12–2.21, P <0.001]. Throughout a median follow-up duration of 207 months, there were 1309 recorded fatalities (53.1%), of which 345 cases (14.0%) were attributable to CVD. Participants exhibiting the longest DNAmTIMP1 demonstrated a 80% increasing in the risk of all-cause mortality (hazard ratio (HR): 1.80, 95% CI: 1.28–2.53, P < 0.001) and a 102% augment in mortality due to CVD (HR: 2.02, 95% CI: 1.05–3.90, P =0.035) when compared to those with the shortest DNAmTIMP1. Conclusion This study provides evidence of a significant positive association between DNAmTIMP1 levels and both cardiovascular disease (CVD) risk and mortality in a middle-aged to older US population. Higher DNAmTIMP1 levels correlate with an increased likelihood of CVD and a higher risk of all-cause and CVD-related mortality. These findings suggest that DNAmTIMP1 may serve as a valuable biomarker for CVD risk assessment and long-term mortality prediction. Further research is needed to elucidate the underlying mechanisms linking DNAmTIMP1 to CVD and mortality, and to explore potential interventions to improve cardiovascular outcomes and reduce mortality rates.