Two Molecular Forms of Adrenomedullin in Congenital Heart Disease K. Watanabe, 1 T. Nishikimi, 2 M. Takamuro, 1 K. Yasuda, 1 Y. Ishikawa, 1 S. Tanabe, 1 O. Yamada, 1 N. Nagaya, 2 H. Matsuoka, 2 K. Kangawa, 4 S. Echigo 1 1 Department of Pediatrics, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan 2 Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu, Tochigi 321-0293, Japan 3 Division of Cardiology, Department of Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan 4 Research Institute, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan Abstract. To investigate the pathophysiological role oftwoformsofadrenomedullin(AM),amatureAM (AM-m) and a glycine-extended AM (AM-Gly), in congenital heart disease, we measured plasma levels of AM in patients with cyanotic heart disease, high pulmonary blood flow without pulmonary hyperten- sion (PH), high pulmonary blood flow with PH, Fontan procedure, intracardiac repair without com- plication, and intracardiac repair with PH and con- trol subjects. Plasma AM-m and AM-Gly were increased only for cyanotic heart disease (2.5 ± 1.3 pmol/L, p < 0.001; 13.1 ± 6.2 pmol/L, p < 0.05) andintracardiacrepairwithPH(2.3±1.5pmol/L, p < 0.01; 13.0 ± 7.0 pmol/L, p < 0.05) compared with control (1.0 ± 1.4 and 8.6 ± 1.3 pmol/L, re- spectively). They were similarly correlated with mean systemic arterial pressure (r = )0.40 and )0.37 re- spectively; p < 0.001), mixed venous oxygen satura- tion (r = )0.60 and )0.50; p < 0.0001), systemic arterial oxygen saturation (SA sat ) (r = )0.56 and )0.46; p <0.0001),andpulmonaryarterialresistance (Rp) (r = 0.41 and 0.38; p < 0.005). Multiple re- gression analysis revealed that SA sat and Rp were independently correlated with AM. Interestingly, the venous AM-m level was significantly higher than the arterial AM-m, suggesting that the mature form is extracted in pulmonary circulation, whereas there were no venoarterial differences in AM-Gly. These results suggest that plasma AM-m and AM-Gly are similarly regulated and the main clearance site of AM-m is the lung in patients with congenital heart disease. Keywords: Adrenomedullin — Congenital heart dis- ease — Hypoxia — Pulmonary hypertension Adrenomedullin (AM) is a 52-amino acid peptide that was originally discovered in acid extracts from human pheochromocytoma [11]. Subsequent studies demonstrated that AM has various physiological ef- fects on the cardiovascular system, including vaso- dilatation [5, 24], diuresis [3], natriuresis [23], inhibition of aldosterone secretion [15, 37], and in- creasing cardiac output [4, 34]. Plasma AM levels increase in proportion to the severity of cardiovas- cular disease, such as heart failure [9, 28], hyperten- sion[8,33],renalfailure[8,36],myocardialinfarction [14, 19], and pulmonary hypertension [10, 27]. Two studies have shown that intravenous AM infusion improves hemodynamics and renal function in pa- tientswithheartfailurewithanincreaseofplasaAM levels within pathophysiological range [15, 23]. These findings suggest that plasma AM may participate in the regulation of circulatory homeostasis and path- ophysiology of cardiovascular disease. However, there are few reports regarding the behavior and significance of AM in congenital heart disease [39]. Human AM precursor consists of 185 amino acids with a putative signal peptide [13]. AM is pro- duced from AM precursor by a two-step enzymatic reaction. First, AM precursor is converted to C- terminal glycine-extended AM (AM-Gly), a 53- amino acid peptide of an intermediate inactive form of AM. Subsequently, inactive AM-Gly is converted to the active form of mature AM (AM-m), a 52- amino acid peptide with a C-terminal amide struc- ture, by enzymatic amidation. Kitamura et al. [12] reported that AM-m and AM-Gly actually circulate in human blood. Correspondence to: T. Nishikimi, email: nishikim@dokkyomed. ac.jp Pediatr Cardiol 24:559–565, 2003 DOI: 10.1007/s00246-003-0321-x