Molecular forms of adrenomedullin in pericardial fluid and plasma in patients with ischaemic heart disease

Abstract

Experimental studies have demonstrated that adrenomedullin (AM) has a positive inotropic action and exerts inhibitory effects against ventricular remodelling as an autocrine and paracrine factor. However, there is no clinical evidence for AM acting as a local regulator in the human heart. We measured the levels of various molecular forms of AM, i.e. an active form of mature AM (AM-m), an intermediate inactive form of glycine-extended AM (AM-Gly) and total AM (AM-T=AM-m+AM-Gly), in plasma and pericardial fluid using our newly developed immunoradiometric assay in consecutive 67 patients undergoing coronary artery bypass graft surgery. Pericardial fluid and plasma cAMP, atrial natriuretic peptide and brain natriuretic peptide levels were also measured. The relationships between pericardial fluid AM levels and ventricular functions and other hormone levels were analysed. The level of each molecular form of AM in pericardial fluid was closely correlated with that of the other molecular forms of AM in the fluid. However, levels were not correlated with those in plasma. AM-T levels were slightly higher in pericardial fluid than in plasma (+72%; P<0.05), whereas AM-m levels and AM-m/AM-T ratios were markedly higher in pericardial fluid than in plasma (AM-m, +994%; AM-m/AM-T ratio, +443%; both P<0.01). AM-m, AM-Gly and AM-T levels in pericardial fluid were correlated with indices of left ventricular function, and with atrial natriuretic peptide and brain natriuretic peptide levels. Interestingly, AM and cAMP levels were positively correlated in plasma, but negatively correlated in pericardial fluid. In addition, AM-m, AM-Gly and AM-T levels in pericardial fluid were higher in patients with acute coronary syndrome than in those with stable ischaemic heart disease (AM-m, +80%; AM-Gly, +96%; AM-T, +83%; all P<0.01). These results suggest that AM in pericardial fluid reflects cardiac synthesis, and that enhanced cardiac secretion of AM is associated with left ventricular dysfunction, ventricular overload and myocardial ischaemia. Considering that AM has positive inotropic, coronary vasodilatory and anti-remodelling actions, increased cardiac AM may play a compensatory role in the ischaemic and failing myocardium.

Diversity of molecular forms of plasma brain natriuretic peptide in heart failure--different proBNP-108 to BNP-32 ratios in atrial and ventricular overload

“…Pericardial fluid contains abundant various bioactive substances produced in the heart10 11 and its composition is similar to the interstitial fluid in the ventricle 19. In addition, the concentrations of bioactive substances, such as adrenomedullin, BNP, ANP, basic fibroblast growth factor and vascular endothelial growth factor, are higher in pericardial fluid than in plasma 12 13 19 20. Our study demonstrated that most IR-BNP is present as IR-proBNP-108, irrespective of the type of heart failure.…”

“…Immediately after the incision of the pericardium, undiluted pericardial fluid was obtained as reported previously 12 13. At the same time, blood was withdrawn from the cannulated brachial artery.…”

Relationships between plasma adrenomedullin concentration and systolic time intervals during static handgrip in patients with heart failure

“…It has been postulated that ADM acts as a cardiac autocrine and paracrine factor. Cardiac secretion of ADM is associated with left ventricular dysfunction, ventricular overload and myocardial ischemia (Nishikimi et al. , 2002, 2004).…”

Increased levels of circulating adrenomedullin following treatment with TU-100 in patients with Crohn's disease

“…Detection of ADM blood plasma levels. ADM occurs in two molecular forms, the active and mature ADM (m-ADM) form and the inactive and glycine-extended ADM (gly-ADM) form (22). Total ADM (t-ADM) is the sum of the levels of m-ADM and gly-ADM.…”