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The Adrenomedullin system in acute dyspnea and cardiometabolic disease

Bronton, Kevin LU orcid (2026) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Background
Adrenomedullin (ADM) is a vasoactive neurohormonal peptide involved in vascular integrity and fluid homeostasis. Even if elevated ADM is an established marker of acute vascular stress, it remains unclear how the ADM system should be measured and interpreted in the general population. In particular, it is uncertain which components of the pathway are most informative, when they should be measured, and how differences in ADM concentrations should be understood. Addressing these questions may help clarify why the same biological system is associated with both acute vascular dysfunction and longer term metabolic risk. This thesis therefore examined the ADM system across acute clinical and population-based settings using... (More)
Background
Adrenomedullin (ADM) is a vasoactive neurohormonal peptide involved in vascular integrity and fluid homeostasis. Even if elevated ADM is an established marker of acute vascular stress, it remains unclear how the ADM system should be measured and interpreted in the general population. In particular, it is uncertain which components of the pathway are most informative, when they should be measured, and how differences in ADM concentrations should be understood. Addressing these questions may help clarify why the same biological system is associated with both acute vascular dysfunction and longer term metabolic risk. This thesis therefore examined the ADM system across acute clinical and population-based settings using molecular epidemiological methods.

Methods
Four studies were conducted using observational clinical and population-based cohorts. Paper I evaluated ADM in patients presenting to the emergency department with acute dyspnea, with 90-day mortality and hospitalization as outcomes. Papers II and IV examined ADM and related precursor peptides glycine-extended ADM, stable prohormone fragment midregional-proADM and peptidylglycine α-amidating monooxygenase (PAM) activity, in relation to diabetes, insulin resistance and adiposity. Paper III used loss of function genetic variants to investigate associations between genetically impaired PAM function and metabolic and body-composition traits.

Results
In the clinical setting of acute dyspnea, higher circulating ADM concentrations were associated with greater risks of 90-day mortality and hospitalization. In the population-based setting ADM was associated with metabolic dysfunction and prospectively with incident diabetes mellitus. Genetically impaired PAM function was associated with worse glucose tolerance and lower muscle mass. Longitudinal analyses suggested that the ADM-system primarily reflected current adiposity and metabolic dysfunction, rather than future changes in weight.

Conclusion
Collectively, the findings support ADM as a context-dependent marker of vascular and metabolic stress, whose triggers and consequences vary across clinical settings and tissues. The predominant observational design does not establish causality. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Juonala, Markus, Turku University
organization
publishing date
type
Thesis
publication status
published
subject
keywords
adrenomedullin, peptidyl-glycine alpha-amidating monooxygenase, dyspnea, diabetes, ADM, PAM
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2026:124
pages
89 pages
publisher
Lund University, Faculty of Medicine
defense location
Jubileumsaulan, Jan Waldenströms gata 1, Skånes Universitetssjukhus i Malmö
defense date
2026-10-02 13:00:00
ISSN
1652-8220
ISBN
978-91-8021-922-8
language
English
LU publication?
yes
id
b88c4eb6-2a83-44b3-914b-f72ab92a94c6
date added to LUP
2026-09-07 20:01:37
date last changed
2026-09-11 10:39:10
@phdthesis{b88c4eb6-2a83-44b3-914b-f72ab92a94c6,
  abstract     = {{<b>Background</b><br/>Adrenomedullin (ADM) is a vasoactive neurohormonal peptide involved in vascular integrity and fluid homeostasis. Even if elevated ADM is an established marker of acute vascular stress, it remains unclear how the ADM system should be measured and interpreted in the general population. In particular, it is uncertain which components of the pathway are most informative, when they should be measured, and how differences in ADM concentrations should be understood. Addressing these questions may help clarify why the same biological system is associated with both acute vascular dysfunction and longer term metabolic risk. This thesis therefore examined the ADM system across acute clinical and population-based settings using molecular epidemiological methods.<br/><br/><b>Methods</b><br/>Four studies were conducted using observational clinical and population-based cohorts. Paper I evaluated ADM in patients presenting to the emergency department with acute dyspnea, with 90-day mortality and hospitalization as outcomes. Papers II and IV examined ADM and related precursor peptides glycine-extended ADM, stable prohormone fragment midregional-proADM and peptidylglycine α-amidating monooxygenase (PAM) activity, in relation to diabetes, insulin resistance and adiposity. Paper III used loss of function genetic variants to investigate associations between genetically impaired PAM function and metabolic and body-composition traits.<br/><br/><b>Results</b><br/>In the clinical setting of acute dyspnea, higher circulating ADM concentrations were associated with greater risks of 90-day mortality and hospitalization. In the population-based setting ADM was associated with metabolic dysfunction and prospectively with incident diabetes mellitus. Genetically impaired PAM function was associated with worse glucose tolerance and lower muscle mass. Longitudinal analyses suggested that the ADM-system primarily reflected current adiposity and metabolic dysfunction, rather than future changes in weight.<br/><br/><b>Conclusion</b><br/>Collectively, the findings support ADM as a context-dependent marker of vascular and metabolic stress, whose triggers and consequences vary across clinical settings and tissues. The predominant observational design does not establish causality.}},
  author       = {{Bronton, Kevin}},
  isbn         = {{978-91-8021-922-8}},
  issn         = {{1652-8220}},
  keywords     = {{adrenomedullin; peptidyl-glycine alpha-amidating monooxygenase; dyspnea; diabetes; ADM; PAM}},
  language     = {{eng}},
  number       = {{2026:124}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{The Adrenomedullin system in acute dyspnea and cardiometabolic disease}},
  url          = {{https://lup.lub.lu.se/search/files/260214615/The_adrenomedullin_system_thesis_Bronton.pdf}},
  year         = {{2026}},
}