Association of Systemic Thromboxane Generation With Risk of Developing Heart Failure

Background: Systemic thromboxane A₂ generation, which is readily assessed by quantifying thromboxane B₂ metabolites (TXB₂-M) in the urine, is associated with impaired cardiac performance and mortality in aspirin (ASA) users with heart failure (HF).

Objectives: This study sought to determine the association of urinary TXB₂-M with the risk of developing HF in individuals without prior history of HF and with normal left ventricular function irrespective of ASA use.

Methods: Urine TXB₂-M were measured by immunoassay and adjusted to urine concentration and renal function (TXB₂-M_GFR) in 2,611 Framingham Heart Study participants (54.9% women, mean age 65 ± 9 years, 43.8% ASA users) without prior history of HF and with left ventricular ejection fraction (LVEF) ≥55%. The association of TXB₂-M_GFR with HF risk over a median observation period of 14.8 years (Q1-Q3: 12.6-15.7 years) was modeled using Cox regression.

Results: HF occurred in 189 participants (7.2%), with 104 of the first events (55.0%) classified as HF with preserved LVEF, 56 (29.6%) as HF with reduced LVEF, and 29 (15.3%) were unclassifiable. TXB₂-M_GFR levels, above compared to below, of 16.6 and 62.1 filtered prostanoid units for ASA users and nonusers, respectively, were associated with increased risk of developing HF (HR: 1.81; 95% CI: 1.38-2.64; P < 0.0001, adjusted for age, sex, ASA use, and HF risk factors), including both HF subtypes (HF with preserved LVEF: HR: 1.81; 95% CI: 1.17-2.80; P = 0.0081, and HF with reduced LVEF: HR: 2.63; 95% CI: 1.48-4.68; P = 0.0010, adjusted for age, sex, ASA use, and cardiovascular disease). Neither ASA use nor evidence of platelet activation, as measured by plasma P-selectin, were independently associated with HF risk.

Conclusions: Systemic thromboxane A₂ generation as measured by urinary TXB₂-M_GFR was significantly associated with HF risk and remained so after accounting for traditional risk factors. Urinary TXB₂-M_GFR is therefore a potentially useful novel biomarker to identify at-risk individuals who might benefit from aggressive primary prevention.