Adrenomedullin as a Biomarker of Heart Failure Toshio Nishikimi, MD, PhD a,b, *, Yasuaki Nakagawa, MD, PhD a INTRODUCTION A number of neurohumoral factors contribute to cardiovascular regulation and to the pathophysi- ology of heart failure. 1 Among these is adrenome- dullin (AM), a potent, long-lasting, vasodilatory peptide originally discovered in the acid extract of human pheochromocytoma tissue. 2 AM expression is widely distributed in the cardiovas- cular system, including the heart, blood vessels, and kidneys. 3 In addition, AM and its receptor components, which include calcitonin receptor- like receptor and receptor activity modifying pro- tein (RAMP)2 and RAMP3, colocalize in those regions, suggesting AM acts in an autocrine and/or paracrine fashion to exert its effects on cardiovascular function. 4 Those effects of AM include positive inotropy and inhibitory effects on cardiomyocyte hypertrophy and proliferation and collagen production in cardiac fibroblasts. 4 This suggests AM acts as an antifibrotic, antihy- pertrophic, and positive inotropic factor in the failing heart. 5 In addition, antiapoptotic, angio- genic, anti-inflammatory and antioxidant effects of AM have also been reported. 6 This suggests AM plays a protective role during heart failure. Indeed, acute administration of AM during exper- imental 7 and human heart failure 8 has been shown to exert beneficial vasodilatory, diuretic, natriuretic, and positive inotropic effects. Here, we review recent study results and describe the significance of AM as a biomarker in heart failure. Adrenomedullin Assays and Absolute Plasma Adrenomedullin Levels in Healthy Subjects AM is produced from its precursor in a 2-step enzymatic reaction. 6 First, the AM precursor Disclosure Statement: There is no conflict of interest to disclose. This study was supported in part by Scientific Research Grants-in-Aid 25126712, 15K09138 (to T. Nishikimi), and 16K09498 (to Y. Nakagawa) from the Ministry of Education, Culture, Sports, Science and Technology of Japan. a Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, 54, Shogoin- Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan; b Department of Medicine, Wakakusa-Tatsuma Rehabilitation Hospital, 1580 Tatsuma, Daito City, Osaka 574-0012, Japan * Corresponding author. Department of Cardiovascular Medicine, Kyoto University Graduate School of Med- icine, 54, Shogoin-Kawara-cho, Sakyo-ku, Kyoto 606-8507, Japan. E-mail address: nishikim@kuhp.kyoto-u.ac.jp KEYWORDS  Adrenomedullin  Heart failure  Mid-regional pro-adrenomedullin  B-type natriuretic peptide (BNP) KEY POINTS  Adrenomedullin (AM) assays and absolute plasma AM levels in healthy subjects.  Two molecular forms of AM: AM-mature and AM-glycine.  Origin of plasma AM and its metabolic clearance.  Plasma AM levels in heart failure.  Plasma mid-regional pro-adrenomedullin levels as a prognostic indicator of heart failure.  Pathophysiological significance of plasma AM in heart failure. Heart Failure Clin - (2017) -–- http://dx.doi.org/10.1016/j.hfc.2017.08.006 1551-7136/17/Ó 2017 Elsevier Inc. All rights reserved. heartfailure.theclinics.com