Journal
JOURNAL OF CARDIAC FAILURE
Volume 19, Issue 4, Pages 219-224Publisher
CHURCHILL LIVINGSTONE INC MEDICAL PUBLISHERS
DOI: 10.1016/j.cardfail.2013.02.001
Keywords
Protein-bound homocitrulline; carbamylation; heart failure; kidney; cardiorenal syndrome; oxidative stress
Categories
Funding
- Abbott Laboratories
- Abbott Diagnostics
- Cleveland Heart Lab
- Esperion
- Lilly
- Liposcience
- Merck Co
- Pfizer
- Abbott
- National Institutes of Health [P01HL076491, P01HL103453]
- NIH [P01HL098055, R01HL103866, R01HL103931, P20HL113452]
- Cleveland Clinic Clinical Research Unit of the Case Western Reserve University CTSA [UL1TR 000439-06]
- American Society of Echocardiography
- Glaxosmithkline Pharmaceuticals
- Roche Diagnostics
- AB Sciex through a Center of Innovation grant
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Background: Protein carbamylation, a posttranslational modification promoted during uremia and catalyzed by myeloperoxidase (MPO) at sites of inflammation, is linked to altered protein structure, vascular dysfunction, and poor prognosis. We examine the relationship between plasma protein-bound homocitrulline (PBHCit) levels, a marker of protein lysine residue carbamylation, with cardiorenal function and long-term outcomes in chronic systolic heart failure (HF). Methods and Results: In 115 patients with chronic systolic HF (left ventricular ejection fraction <= 35%), we measured plasma PBHCit by quantitative mass spectrometry and performed comprehensive echocardiography with assessment of cardiac structure and performance. Adverse long-term events (death, cardiac transplantation) were tracked for 5 years. In our study cohort, the median PBHCit level was 87 (interquartile range 59-128) mu mol/mol lysine. Higher plasma PBHcit levels were associated with poorer renal function (estimated glomerular filtration rate [eGFR]: Spearman r = -0.37; P < .001), cystatin C (r = 0.31; P = .001), and elevated plasma amino-terminal pro B-type natriuretic peptide (NT-proBNP) levels (r = 0.26; P = .006), but not with markers of systemic inflammation or oxidant stress (high-sensitivity C-reactive protein and myeloperoxidase [MPO]: P > .10 for each). Furthermore, elevated plasma PBHCit levels were not related to indices of cardiac structure or function (P > .10 for all examined) except modestly with increased right atrial volume index (r = 0.31; P = .002). PBHCit levels predicted adverse long-term events (hazard ratio [HR] 1.8, 95% confidence interval [CI] 1.3-2.6; P < .001), including after adjustment for age, eGFR, MPO, and NT-proBNP (HR 1.9, 95% CI 1.2-3.1; P = .006). Conclusions: In chronic systolic HF, protein carbamylation is associated with poorer renal but not cardiac function, and portends poorer long-term adverse clinical outcomes even when adjusted for cardiorenal indices of adverse prognosis. (J Cardiac Fail 2013;19:219-224)
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