Protein carbamylation in chronic systolic heart failure: relationship with renal impairment and adverse long-term outcomes

J Card Fail. 2013 Apr;19(4):219-24. doi: 10.1016/j.cardfail.2013.02.001. Epub 2013 Mar 19.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Blood Proteins / metabolism
  • Chronic Disease
  • Citrulline / analogs & derivatives*
  • Citrulline / blood
  • Cohort Studies
  • Female
  • Heart Failure, Systolic / blood*
  • Heart Failure, Systolic / diagnosis*
  • Heart Failure, Systolic / therapy
  • Humans
  • Kidney Diseases / blood*
  • Kidney Diseases / diagnosis*
  • Kidney Diseases / therapy
  • Male
  • Middle Aged
  • Prospective Studies
  • Protein Binding / physiology
  • Time Factors
  • Treatment Outcome

Substances

  • Blood Proteins
  • homocitrulline
  • Citrulline