DOI: 10.1161/jaha.126.054269 ISSN: 2047-9980

Urinary Metals, Soluble Urokinase Plasminogen Activator Receptor, and Outcomes in the Multi‐Ethnic Study of Atherosclerosis

Bahjat Z. Ghazzal, Anis Ismail, Theresa Farhat, Yiyuan Huang, Pennelope Blakely, Kathrin Schilling, Ronald Glabonjat, Tiffany R. Sanchez, Irene Martinez‐Morata, Katlyn McGraw, Arce Domingo‐Relloso, Ana Navas‐Acien, Susan R. Heckbert, Salim S. Hayek
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Background

Environmental metal exposure is associated with cardiovascular disease (CVD) and mortality, potentially through inflammation. Soluble urokinase plasminogen activator receptor (suPAR), a stable marker of immune activation associated with CVD and death, may capture this pathway. We examined associations of urinary metals with suPAR and whether suPAR‐associated components were present in cadmium–outcome associations.

Methods

In the Multi‐Ethnic Study of Atherosclerosis, we studied 5,148 adults free of clinical CVD (2000–2002). We estimated associations of 11 creatinine‐standardized urinary metals with serum suPAR by linear regression (per interquartile‐range [IQR] increase), compared associations across suPAR, high‐sensitivity C‐reactive protein (hs‐CRP), interleukin‐6 (IL‐6), and D‐dimer, and used VanderWeele 4‐way decomposition to estimate suPAR‐associated indirect components of cadmium associations with all‐cause mortality and four adjudicated cardiovascular outcomes.

Results

Of 11 metals, 7 were associated with suPAR; cadmium showed the strongest association (7.99% higher suPAR per IQR; 95% CI, 6.14–9.87) followed by cobalt, copper, molybdenum, tungsten, and zinc, whereas barium was inversely associated. The association was monotonic and persisted among never‐smokers (5.54%; 95% CI, 3.03–8.11). Over a median 14.7 years, higher urinary cadmium was associated with all‐cause mortality (Q4‐vs‐Q1 hazard ratio, 1.43; 95% CI, 1.18–1.74); the suPAR‐associated proportion was 0.30 (95% CI, 0.13–0.47).

Conclusions

Cadmium showed a larger association with suPAR than with hs‐CRP, IL‐6, or D‐dimer. An exploratory decomposition identified a suPAR‐associated component of this association. Findings for cardiovascular outcomes were directionally consistent but not definitive. suPAR‐related immune activation is a candidate pathway linking cadmium to mortality, warranting longitudinal and mechanistic confirmation.

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