What is Pro-adrenomedullin?
Pro-adrenomedullin is a precursor peptide hormone that is cleaved to produce several bioactive fragments, including midregional pro-adrenomedullin (MR-proADM), which serves as a stable biomarker for risk stratification and mortality prediction in acute conditions like sepsis, heart failure, and community-acquired pneumonia.
Biochemistry and Processing
Pro-adrenomedullin is processed into multiple fragments with distinct biological roles 1:
- Midregional pro-adrenomedullin (MR-proADM): A stable fragment that serves as a surrogate marker for adrenomedullin activity, with a longer half-life than the active peptide 2
- Glycine-extended adrenomedullin (ADM-Gly): The direct precursor of bioactive adrenomedullin and the predominant form in healthy human plasma 1
- Bioactive adrenomedullin (bio-ADM): The active form with vasodilatory, anti-inflammatory, and angiogenic properties but a very short plasma half-life 3, 1
The peptide is primarily secreted from vascular endothelial cells and has multiple physiological actions including vasodilation, regulation of vascular permeability, angiogenesis, and anti-inflammatory effects 3.
Clinical Applications
Heart Failure Risk Stratification
MR-proADM provides independent prognostic information beyond natriuretic peptides in both acute and chronic heart failure settings 2:
- In the BACH study, MR-proADM was associated with 3-month mortality with prognostic value beyond natriuretic peptides 2
- Above-median MR-proADM levels predicted increased mortality risk (risk ratio 3.92,95% CI 1.76-8.7) and heart failure hospitalization (risk ratio 2.4,95% CI 1.3-4.5) independently of traditional clinical and echocardiographic factors 2
- Treatment with carvedilol reduced adverse outcomes in patients with elevated NT-proBNP, MR-proADM, or both 2
However, the 2017 American Heart Association guidelines note that more studies are needed to determine the full utility and prognostic value of MR-proADM in heart failure 2.
Community-Acquired Pneumonia
Among all biomarkers investigated for pneumonia severity assessment, pro-ADM appears most promising 2:
- ProADM levels increase with increasing pneumonia severity as classified by the Pneumonia Severity Index (p < 0.001) 4
- In patients who died during follow-up, proADM levels on admission were significantly higher compared to survivors (2.1 vs 1.0 nmol/L, p < 0.001) 4
- The area under the ROC curve for proADM (0.76) was significantly higher than procalcitonin, C-reactive protein, and leukocyte count for predicting mortality 4
- Adding proADM to the Pneumonia Severity Index improved prognostic accuracy (AUC 0.77 vs 0.73, p = 0.03) 4
The 2011 European guidelines for lower respiratory tract infections specifically highlight that pro-ADM seems most promising among all biomarkers investigated for pneumonia severity assessment 2.
Sepsis and Septic Shock
MR-proADM can predict organ damage and imminent death risk in patients with septic shock 5:
- It serves as a prognostic biomarker to stratify mortality risk in sepsis with different degrees of organ damage 5
- Testing MR-proADM in the emergency department may improve prognostic assessment and facilitate clinical management decisions 5
Current Guideline Recommendations
The 2021 ESC guidelines for acute coronary syndromes explicitly do NOT recommend routine measurement of mid-regional pro-adrenomedullin for risk or prognosis assessment 2. This recommendation (Class III, Level B) applies to the acute coronary syndrome population specifically, where other biomarkers like high-sensitivity troponin and natriuretic peptides have more established roles.
Important Caveats
- Pro-adrenomedullin and its fragments have different hormonal profiles and may differentially modulate cardiovascular function despite being processed from the same precursor 6
- Plasma PAMP (proadrenomedullin N-terminal 20 peptide) concentrations are typically one-fifth to one-seventh of adrenomedullin levels 6
- While MR-proADM shows promise in multiple acute conditions, its role remains primarily investigational outside of research settings, with the exception of pneumonia severity assessment where it has the strongest evidence 2