Frederik H. Verbrugge

Protein carbamylation and cardiovascular disease

Carbamylation constitutes a posttranslational modification of proteins or amino acids and results from different pathways in vivo. First is the non-enzymatic reaction between isocyanic acid, a decomposition product of urea, and either the N-terminus or ε-amino group of lysine residues. Isocyanic acid levels, while low in vivo, are in equilibrium with urea, and are thus increased in chronic and end-stage renal diseases. An alternative pathway involves the leukocyte haem protein myeloperoxidase, which catalyses the oxidation of thiocyanate in the presence of hydrogen peroxide, producing isocyanate at inflammation sites. Notably, plasma thiocyanate levels are increased in smokers, and leukocyte-driven protein carbamylation occurs both within human and animal atherosclerotic plaques, as well as on plasma proteins. Protein carbamylation is considered a hallmark of molecular aging and is implicated in many pathological conditions. Recently, it has been shown that carbamylated low-density lipoprotein (LDL) induces endothelial dysfunction via lectin-like-oxidized LDL receptor-1 activation and increased reactive oxygen species production, leading to endothelial nitric oxide synthase uncoupling. Moreover, carbamylated LDL harbours atherogenic activities, including both binding to macrophage scavenger receptors inducing cholesterol accumulation and foam cell formation, as well as promoting vascular smooth muscle proliferation. In contrast, high-density lipoprotein loses its anti-apoptotic activity after carbamylation, contributing to endothelial cell death. In addition to involvement in atherogenesis, protein carbamylation levels have emerged as a particularly strong predictor of both prevalent and incident cardiovascular disease risk. Recent studies also suggest that protein carbamylation may serve as a potential therapeutic target for the prevention of atherosclerotic heart disease.

Response and tolerance to oral vasodilator up-titration after intravenous vasodilator therapy in advanced decompensated heart failure

The aim of this study was to assess the haemodynamic response and tolerance to aggressive oral hydralazine/isosorbide dinitrate (HYD/ISDN) up‐titration after intravenous vasodilator therapy in advanced decompensated heart failure (ADHF).