Ceruloplasmin and Heart Failure in the Atherosclerosis Risk in Communities Study

Abstract

Background Ceruloplasmin (Cp) decreases nitric oxide bioavailability in blood and has been associated with cardiovascular disease (CVD) in clinical studies. We assessed the association between Cp and incident heart failure (HF), death and CVD in the Atherosclerosis Risk in Communities (ARIC) Study. Methods and Results Cp was measured at ARIC visit 4 (1996–1998). We studied 9,240 individuals without HF or CVD at ARIC visit 4, and followed them for a mean of 10.5 years. Genome-wide association study was performed to identify genetic determinants of Cp levels and evaluate their association with incident HF. Cp levels (mean±standard deviation) were higher in women vs men (335±79 vs 258±44 mg/L, p<0.0001), women on vs not on hormone-replacement therapy (398±89 vs 291±60 mg/L, p<0.0001) and African Americans vs Caucasians (299±63 vs 293±74 mg/L, p=0.0005). After adjusting for traditional risk factors, high-sensitivity C-reactive protein, N-terminal pro–B-type natriuretic peptide, and high-sensitivity cardiac troponin T, higher levels of Cp were associated with HF (hazard ratio [HR] 1.44, 95% confidence interval [CI] 1.13–1.83) and mortality (HR 1.38, 95% CI 1.11–1.63). A locus on the ceruloplasmin gene on chromosome 3 was significantly associated with Cp levels (normal 295.56±77.60mg/L, heterozygote 316.72±88.02mg/L; homozygote 331.04±85.40mg/L, p=8.3×10−) but not with incident HF. After adjustment for traditional risk factors Cp levels were also weekly associated with CVD. Conclusions Cp was associated with incident, HF mortality and CVD in the ARIC population. A single locus on chromosome 3 was associated with Cp levels but not with HF.

Role of Biomarkers for the Prevention, Assessment, and Management of Heart Failure: A Scientific Statement From the American Heart Association

“…Higher levels of ceruloplasmin have been linked to new-onset HF in the ARIC study (Atherosclerosis Risk in Communities). 60 Furthermore, inflammatory markers have been evaluated for predicting new-onset HF. In the ABC study (Health, Aging, and Body Composition), IL-6, tumor necrosis factor-α, and CRP were associated with new-onset HF, but when all 3 markers were added to the model, IL-6 emerged as the strongest marker.…”

Low Serum Ferroxidase I Activity Is Associated With Mortality in Heart Failure and Related to Both Peroxynitrite-Induced Cysteine Oxidation and Tyrosine Nitration of Ceruloplasmin

“…8,9 As a matter of fact, our findings show that ceruloplasmin and FeOxI were unrelated in patients with HF with pooled preserved and reduced EF. It is unclear why ceruloplasmin had no predictive value in our patients with HF, the majority (81%) of whom had an ischemic origin.…”

“…It is unclear why ceruloplasmin had no predictive value in our patients with HF, the majority (81%) of whom had an ischemic origin. However, the population enrolled in our study was significantly older (mean age, 76 years old), included patients with advanced stages of heart failure (≈60% with mean EF of 34%) compared with the younger patients in the 2 larger studies by Tang et al 8 and Dadu et al 9 (mean age, 62 years old) and at least in the Atherosclerosis Risk in Communities Study in subjects without heart failure and cardiovascular disease at enrollment. 9 Only FeOxI was found to predict the mortality risk, and a close inverse relationship was found with nitrotyrosine-bound ceruloplasmin in both patients with HF with preserved and reduced EF and with hsCRP in patients with HF with reduced EF.…”

“…However, the population enrolled in our study was significantly older (mean age, 76 years old), included patients with advanced stages of heart failure (≈60% with mean EF of 34%) compared with the younger patients in the 2 larger studies by Tang et al 8 and Dadu et al 9 (mean age, 62 years old) and at least in the Atherosclerosis Risk in Communities Study in subjects without heart failure and cardiovascular disease at enrollment. 9 Only FeOxI was found to predict the mortality risk, and a close inverse relationship was found with nitrotyrosine-bound ceruloplasmin in both patients with HF with preserved and reduced EF and with hsCRP in patients with HF with reduced EF. In addition, the analysis of hospitalization rate of our patient population showed that time to first admission was much shorter in patients with low FeOxI activity, whereas no difference in number of hospital admission during the follow-up period was observed among FeOxI tertiles.…”

“…4,7 It has been recently reported that high ceruloplasmin circulating levels have an independent prognostic value in stable patients undergoing elective diagnostic cardiac catheterization procedure 8 and are associated with the incidence of HF and mortality in the Atherosclerosis Risk in Communities study population. 9 In another prospective study, a relationship between serum ceruloplasmin levels and the subsequent development of myocardial infarction in the elderly general population was reported. 10 In settings of experimental and human HF, increased peroxynitrite generation, from nitric oxide and superoxide or from hemoperoxidases, 6 leads to extensive tyrosine protein nitration.…”