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) μmol/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.
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) μmol/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.
Authors: Eugene O Apostolov; Debarti Ray; Alena V Savenka; Sudhir V Shah; Alexei G Basnakian Journal: J Am Soc Nephrol Date: 2010-10-14 Impact factor: 10.121
Authors: Zeneng Wang; Stephen J Nicholls; E Rene Rodriguez; Outi Kummu; Sohvi Hörkkö; John Barnard; Wanda F Reynolds; Eric J Topol; Joseph A DiDonato; Stanley L Hazen Journal: Nat Med Date: 2007-09-09 Impact factor: 53.440
Authors: Michael Holzer; Martin Gauster; Thomas Pfeifer; Christian Wadsack; Guenter Fauler; Philipp Stiegler; Harald Koefeler; Eckhard Beubler; Rufina Schuligoi; Akos Heinemann; Gunther Marsche Journal: Antioxid Redox Signal Date: 2011-03-28 Impact factor: 8.401
Authors: Kathryn C B Tan; Ching-Lung Cheung; Alan C H Lee; Joanne K Y Lam; Ying Wong; Sammy W M Shiu Journal: Clin J Am Soc Nephrol Date: 2020-02-19 Impact factor: 8.237
Authors: Jeffrey Perl; Sahir Kalim; Ron Wald; Marc B Goldstein; Andrew T Yan; Nazanin Noori; Mercedeh Kiaii; Julia Wenger; Christopher Chan; Ravi I Thadhani; S Ananth Karumanchi; Anders H Berg Journal: Hemodial Int Date: 2016-06-21 Impact factor: 1.812
Authors: Sahir Kalim; Caitlin A Trottier; Julia B Wenger; Josh Wibecan; Rayhnuma Ahmed; Elizabeth Ankers; S Ananth Karumanchi; Ravi Thadhani; Anders H Berg Journal: Clin J Am Soc Nephrol Date: 2016-07-21 Impact factor: 8.237
Authors: Lixia Zeng; Anna V Mathew; Jaeman Byun; Kevin B Atkins; Frank C Brosius; Subramaniam Pennathur Journal: J Biol Chem Date: 2018-03-26 Impact factor: 5.157
Authors: Sahir Kalim; Guillermo Ortiz; Caitlin A Trottier; Joseph J Deferio; S Ananth Karumanchi; Ravi I Thadhani; Anders H Berg Journal: J Ren Nutr Date: 2015-03-05 Impact factor: 3.655