Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases

Toshihiro Kita, Kazuo Kitamura, Toshihiro Kita, Kazuo Kitamura

Abstract

Adrenomedullin (AM) is a vasodilative peptide with various physiological functions, including the maintenance of vascular tone and endothelial barrier function. AM levels are markedly increased during severe inflammation, such as that associated with sepsis; thus, AM is expected to be a useful clinical marker and therapeutic agent for inflammation. However, as the increase in AM levels in cardiovascular diseases (CVDs) is relatively low compared to that in infectious diseases, the value of AM as a marker of CVDs seems to be less important. Limitations pertaining to the administrative route and short half-life of AM in the bloodstream (<30 min) restrict the therapeutic applications of AM for CVDs. In early human studies, various applications of AM for CVDs were attempted, including for heart failure, myocardial infarction, pulmonary hypertension, and peripheral artery disease; however, none achieved success. We have developed AM as a therapeutic agent for inflammatory bowel disease in which the vasodilatory effect of AM is minimized. A clinical trial evaluating this AM formulation for acute cerebral infarction is ongoing. We have also developed AM derivatives that exhibit a longer half-life and less vasodilative activity. These AM derivatives can be administered by subcutaneous injection at long-term intervals. Accordingly, these derivatives will reduce the inconvenience in use compared to that for native AM and expand the possible applications of AM for treating CVDs. In this review, we present the latest translational status of AM and its derivatives.

Keywords: Adrecizumab; Adrenomedullin; Clinical trial; PEGylated adrenomedullin; Translational research.

Conflict of interest statement

The authors declare no competing interests.

© 2021. The Author(s), under exclusive licence to The Japanese Society of Hypertension.

Figures

Fig. 1
Fig. 1
Plasma concentrations of bioactive adrenomedullin (ADM) in various diseases and the maximum concentration (Cmax) used in our current trials. The assay systems used in the studies referred to in the upper and lower parts of the figure used different antibodies. As a result, AM concentrations in studies shown in the lower section of the figure are lower than those shown in the upper section. Plasma concentrations in the SAH study and clinical trials are shown as the mean ± SD. All others are shown as the median with the interquartile range. ARDS, acute respiratory distress syndrome; COVID-19, coronavirus disease 2019; AHF, acute heart failure; ACS, acute coronary syndrome; CHF, congestive heart failure; SAH, subarachnoid hemorrhage; H & H, Hunt and Hess grading scale; UC, ulcerative colitis
Fig. 2
Fig. 2
Doses of adrenomedullin (AM) used in early studies and recent clinical trials. PA, primary aldosteronism; HT, hypertension; DM, diabetes mellitus; AMI, acute myocardial infarction; CRF, chronic renal failure; EHT, essential hypertension; CHF, congestive heart failure; PH, pulmonary hypertension; UC, ulcerative colitis; CD, Crohn’s disease; CI, cerebral infarction; COVID-19, coronavirus disease 2019
Fig. 3
Fig. 3
Potential applications of adrenomedullin (AM) and PEGylated AM (PEG-AM) in cardiovascular diseases. HF, heart failure

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