Increased dipeptidyl peptidase 4 in patients with concomitant transthyretin cardiac amyloidosis and severe aortic stenosis

Margrethe Flesvig Holt; Annika E Michelsen; August Flø; Kristoffer Russell; Jan Otto Beitnes; Sophie Foss Kløve; Anders Hodt; Lars Gullestad; Pål Aukrust; Einar Gude; Kaspar Broch; Thor Ueland

doi:10.1016/j.ijcha.2025.101820

Increased dipeptidyl peptidase 4 in patients with concomitant transthyretin cardiac amyloidosis and severe aortic stenosis

Int J Cardiol Heart Vasc. 2025 Oct 8:61:101820. doi: 10.1016/j.ijcha.2025.101820. eCollection 2025 Dec.

Authors

Margrethe Flesvig Holt^{1

2

3}, Annika E Michelsen^{2

3}, August Flø^{1

3}, Kristoffer Russell¹, Jan Otto Beitnes¹, Sophie Foss Kløve¹, Anders Hodt⁴, Lars Gullestad^{1

3}, Pål Aukrust^{2

3

5}, Einar Gude¹, Kaspar Broch¹, Thor Ueland^{2

3

6}

Affiliations

¹ Department of Cardiology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
² Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
³ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norway.
⁴ Department of Nuclear Medicine, Oslo University Hospital, Oslo, Norway.
⁵ Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, Oslo, Norway.
⁶ Thrombosis Research Center (TREC), Division of Internal Medicine, University Hospital of North Norway, Tromsø, Norway.

Abstract

Background: Due to overlapping symptoms and signs, it can be challenging to diagnose transthyretin amyloid cardiomyopathy (ATTR-CM) in the setting of concomitant aortic stenosis. Biomarkers may discriminate between heart failure with ATTR-CM and heart failure without ATTR-CM, but it is not known if these markers can differentiate between AS with and AS without concomitant ATTR-CM.

Methods: In 9 patients with ATTR-CM and AS, 161 patients with lone AS, and 23 healthy controls, we measured 8 plasma proteins previously identified by proteomic analysis as potential candidates for diagnosing ATTR-CM. We assessed differences between groups and association with indices of heart failure and AS severity.

Results: Plasma levels of dipeptidyl peptidase 4 (DPP4) were significantly higher in patients with AS and ATTR-CM than in patients with lone AS and in healthy controls. Lower levels of DPP4 were also associated with worse left ventricular function, higher New York Heart Association functional class, and low-flow, low-gradient aortic stenosis.

Conclusions: Our findings suggest that DPP4 may be a marker of ATTR-CM in patients with severe AS. In all AS patients, those with and without coexisting ATTR-CM, high DPP4 levels were asociated with better cardiac function.

Keywords: Aortic stenosis; Decorin; Dipeptidyl peptidase 4; Hepatocyte growth factor; Transthyretin amyloid cardiomyopathy.