Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases

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.

Adrenomedullin Therapy in Moderate to Severe COVID-19

“…et al, are using different antibodies for the measurement of active AM, so our values tend to be lower than Simon, T.P. et al [108]. Moreover, similar results were obtained in patients with UC in a phase 2 trial, namely the concentration of AM reached 5.9 to 7.4 times the basal values; day 1: 67.4 ± 16.0 and day 8: 84.7 ± 48.1 pg/mL [115].…”

“…Progress of Clinical Trials Using AM AM was discovered in 1993, and the first human study was conducted in 1997 [107]. Early studies focused on the vasodilative effect of AM and used a relatively high dose to alter hemodynamics and humoral factors [108]. However, controlling the vasodilative effect of AM in general use is difficult; therefore, AM has not been adopted as a therapeutic agent for cardiovascular diseases [108].…”

“…Early studies focused on the vasodilative effect of AM and used a relatively high dose to alter hemodynamics and humoral factors [108]. However, controlling the vasodilative effect of AM in general use is difficult; therefore, AM has not been adopted as a therapeutic agent for cardiovascular diseases [108]. The turning point was discovering the mucosal healing effect of AM in experimental colitis [109].…”

Biomarkers of Volume Overload and Edema in Heart Failure With Reduced Ejection Fraction

“…These results proved that ADM could be a useful marker to identify HF subjects at risk of rehospitalization due to suboptimal decongestion (34). Another study proposed that the stabilizing endothelial barrier effect, could be achieved by administrating 15 ng/kg/min of ADM, thus reducing pulmonary congestion without significant hemodynamic effects (36). Unfortunately, since ADM plasma levels are also very elevated in severe infections (especially in septic status), its use in HF patients must be carefully interpreted.…”

Genetic Modifications to Alter Blood Pressure Level

“…Recently, an alternative pathway mediated by the PIEZO1adrenomedullin (ADM) axis was reported [ 51 ]. ADM is a circulatory vasodilator and diuretic and natriuretic peptide that is mainly produced by ECs [ 52 ]. Iring et al showed that PIEZO1 enhanced endothelial ADM secretion, then the secreted ADM bound to calcitonin receptor-like receptor (CALCRL) on ECs by an autocrine/paracrine fashion.…”