Sex-specific trajectories of cardiovascular risk factors and biomarkers in the decades prior to a cardiovascular event: a pooled cohort of individual participant data

Abstract Background Most previous studies on cardiovascular disease prediction have relied on single measurements of clinical risk factors and circulating biomarkers, while the trajectories of these factors and their relation to adverse cardiovascular outcomes remain largely unexplored. Aim We aimed to characterize and compare sex-specific trajectories of cardiovascular risk factors, kidney function, and circulating biomarkers in relation to cardiovascular events over the adult life course. Methods We analysed individual participant data of four population-based cohort studies (CHS, HUNT, MESA, and Whitehall II), including 59,328 women and 54,284 men, aged 19 to 100 years at baseline. Cardiovascular risk factors, kidney function, and biomarkers (C-reactive protein, cardiac troponin I and T, and N-terminal pro–B-type natriuretic peptide NT-proBNP) were repeatedly measured across 316,719 study visits over a 34-year period (1985 to 2019). The primary outcome was a composite of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death, and occurred in 8,025 (13.5%) women and 8,892 (16.4%) men during a median follow-up of 19 (25th to 75th percentile, 10 to 27) years. We used mixed-effects and multistate joint models to estimate the sex-specific associations between longitudinal trajectories and the primary outcome. Results Trajectories of all cardiovascular risk factors, kidney function, and biomarkers differed significantly between women and men over the life course (Pinteraction0.001 for all). Trajectories also differed between individuals who experienced the primary outcome and those who remained event-free (Figure 1 and Figure 2), with less favorable risk factor profiles in those who experienced the event, some of which were modified by age. Beyond risk factor and biomarker level, the joint models demonstrated statistically significant associations between rate of change (slope) and cumulative exposure (area) of these factors and risk of the primary outcome (for example, HRarea per 0.1 SD log2 NT-proBNP: 1.06 95%CI, 1.05 to 1.07 in women and 1.06 95%CI, 1.05 to 1.07 in men, Pinteraction=0.278). Conclusions Up to three decades prior to first-onset cardiovascular disease, trajectories of cardiovascular risk factors, kidney function, and circulating biomarkers diverge between individuals who experience the event and those who remain event-free, with important differences by sex and age. Dynamic risk profiling that includes trajectories of both conventional and emerging risk factors should be further explored and may refine cardiovascular risk estimates to enhance and personalize disease prevention strategies.For image description, please refer to the figure legend and surrounding text. For image description, please refer to the figure legend and surrounding text.