Combined elevation of Lp(a), hs-CRP and homocysteine triples stroke risk in the Multi-Ethnic Study of Atherosclerosis (Am J Prev Cardiol 2025)

Original title: Lipoprotein(a), high-sensitivity c-reactive protein, homocysteine and cardiovascular disease in the Multi-Ethnic Study of Atherosclerosis

Am J Prev Cardiol · 11 December 2024 · 7

Nomura SO, Bhatia HS, Garg PK, Karger AB, Guan W, Cao J, Shapiro MD, Tsai MY

In 6,676 (CHD) and 6,674 (stroke) MESA participants followed 2000 to 2017, elevated Lp(a) alone was associated with CHD but not stroke, while elevated hs-CRP alone was associated with stroke but not CHD. Risk rose with each additional elevated biomarker: CHD hazard ratio 2.02 (95% CI 1.26, 3.24) when Lp(a), hs-CRP and homocysteine were all elevated, and stroke hazard ratio 2.99 (95% CI 1.61, 5.58) for the same combination, versus hazard ratios of 1.34 to 1.58 for any two elevated together. This multi-ethnic cohort analysis argues for assessing Lp(a) alongside inflammatory and homocysteine markers rather than in isolation when stratifying ASCVD risk.

Original abstract

Background And Aims: Elevated lipoprotein(a) [Lp(a)], high-sensitivity C-Reactive Protein (hs-CRP), and total homocysteine (tHcy) are associated with atherosclerotic cardiovascular disease (ASCVD) risk. This study investigated the individual and joint associations of Lp(a), hs-CRP and tHcy with coronary heart disease (CHD) and stroke.

Methods: This study was conducted in the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (2000-2017) (CHD analytic N = 6,676; stroke analytic N = 6,674 men and women). Associations between Lp(a) (<50 vs. ≥50 mg/dL), hs-CRP (<2 vs. ≥2 mg/L) and tHcy (<12 vs. ≥12 µmol/L) and CHD and stroke incidence were evaluated individually and jointly using Cox proportional hazards regression.

Results: Individually, elevated tHcy was associated with CHD and stroke incidence, Lp(a) with CHD only and hs-CRP with stroke only. In combined analyses, CHD risk was higher when multiple biomarkers were elevated [hs-CRP+Lp(a), hazard ratio (HR)=1.39, 95 % confidence interval (CI): 1.06, 1.82; hs-CRP+ tHcy, HR = 1.34, 95 % CI: 1.02, 1.75; Lp(a)+ tHcy HR = 1.58, 95 % CI: 1.08, 2.30; hs-CRP+Lp(a)+ tHcy HR = 2.02, 95 % CI: 1.26, 3.24]. Stroke risk was elevated when hs-CRP and either Lp(a) (HR = 1.51, 95 % CI: 1.02, 2.23) or tHcy (HR = 2.10, 95 % CI: 1.44, 3.06) was also high, when all three biomarkers were elevated (HR = 2.99, 95 % CI: 1.61, 5.58), or when hs-CRP and tHcy (HR = 1.79, 95 % CI: 1.16, 2.76) were both high.

Conclusions: Risk of ASCVD was highest with concomitant elevation of tHcy, hs-CRP and Lp(a). Inclusion of tHcy and consideration of biomarker combination rather than individual biomarker levels may help better identify individuals at greatest risk for ASCVD events.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.