Healthy Lifestyle, Metabolic Signature, and Risk of Cardiovascular Diseases: A Population-Based Study

Abstract

Background: Although healthy lifestyle has been linked with a reduced risk of cardiovascular diseases (CVDs), the potential metabolic mechanism underlying this association remains unknown.

Methods: We included 161,018 CVD-free participants from the UK Biobank. Elastic net regression was utilized to generate a healthy lifestyle-related metabolic signature. The Cox proportional hazards model was applied to investigate associations of lifestyle-related metabolic signature with incident CVDs, and mediation analysis was conducted to evaluate the potential mediating role of metabolic profile on the healthy lifestyle-CVD association. Mendelian randomization (MR) analysis was conducted to detect the causality.

Results: During 13 years of follow-up, 17,030 participants developed incident CVDs. A healthy lifestyle-related metabolic signature comprising 123 metabolites was established, and it was inversely associated with CVDs. The hazard ratio (HR) was 0.83 (95% confidence interval [CI]: 0.81, 0.84) for CVD, 0.83 (95% CI: 0.81, 0.84) for ischemic heart disease (IHD), 0.86 (95% CI: 0.83, 0.90) for stroke, 0.86 (95% CI: 0.82, 0.89) for myocardial infarction (MI), and 0.75 (95% CI: 0.72, 0.77) for heart failure (HF) per standard deviation increase in the metabolic signature. The metabolic signature accounted for 20% of the association between healthy lifestyle score and CVD. Moreover, MR showed a potential causal association between the metabolic signature and stroke.

Conclusions: Our study revealed a potential link between a healthy lifestyle, metabolic signatures, and CVD. This connection suggests that identifying an individual's metabolic status and implementing lifestyle modifications may provide novel insights into the prevention of CVD.

Keywords: CVD; Mendelian randomization; healthy lifestyle; metabolic signature.

Figure 1

Flowchart of study design and associations between the metabolic signature and healthy lifestyle score. (A) The training and testing procedures of a metabolic signature for the healthy lifestyle. The correlations between healthy lifestyle scores and the metabolic signature in the primary and replication study are shown in (B,C).

Figure 2

Associations between 123 metabolites constituting the metabolic signature and healthy lifestyle components, healthy lifestyle score, and subsequent CVDs. (A) For 61 metabolites. (B) For 62 metabolites. From bottom to top are the metabolites’ coefficients (weights) of the signature and associations with healthy lifestyle component, healthy lifestyle, and CVDs. The coefficients for healthy lifestyle components and the overall healthy lifestyle score represent a one-unit increase per component’s score. Coefficients for CVD risk correspond to per SD increase in metabolites. Colors depict the direction of associations (positive-red and inverse-blue) and their magnitudes (darker shades indicate larger magnitudes); asterisks denote significance levels (* p < 0.05 and ** p < Bonferroni-adjusted 0.05). We used Bonferroni correction for 123 metabolites for the healthy lifestyle score and CVD risk and 123 metabolites × 5 healthy lifestyle components). C indicates cholesterol; CE, cholesteryl ester; FC, free cholesterol; LDL, low-density lipoprotein; M, medium; PL, phospholipid; S, small; VLDL, very LDL; XL, very large; XS, very small; XXL, extra large; SD, standard deviation; CVD, cardiovascular disease; IHD, ischemic heart disease; MI, myocardial infarction; and HF, heart failure.

Figure 3

Proportions mediated by metabolites or the metabolic signature for the association between healthy lifestyle and CVDs risk. (A) Proportion mediated by metabolic pathways for the association between healthy lifestyle score and CVDs risk. (B) Proportion mediated by metabolites constituting the metabolic signature for the association between individual lifestyle factors and CVD risk. Statistical significance was set at p  <  0.05. CVD indicates cardiovascular disease; IHD, ischemic heart disease; MI, myocardial infarction; and HF, heart failure.

Figure 4

MR analyses for the association between the metabolic signature and CVDs risk. Fourteen genetic variants linked to the metabolic signature at p < 1 × 10⁻⁶ were employed as the instrumental variable in the mode-based estimation (MBE) MR analyses following Hartwig’s method. OR indicates odds ratio; CI, confidence interval; MR, Mendelian randomization; CVD, cardiovascular disease; IHD, ischemic heart disease; MI, myocardial infarction; and HF, heart failure.