Circulating ECM proteins decorin and alpha-L-iduronidase differentiate ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF

• Published in: Cardiovascular research 2024-11, Vol.120 (14), p.1727-1736
• Main Authors: Tubben, Alwin, Markousis-Mavrogenis, George, Meems, Laura M G, van Essen, Bart J, Baumhove, Lukas, Berends, Milou, Tingen, Hendrea S A, Bijzet, Johan, Hazenberg, Bouke P C, Voors, Adriaan A, van Veldhuisen, Dirk J, Slart, Riemer H J A, Nienhuis, Hans L A, van der Meer, Peter
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Amyloid Neuropathies, Familial - blood; Amyloid Neuropathies, Familial - diagnosis; Amyloid Neuropathies, Familial - genetics; Biomarkers - blood; Cardiomyopathies - blood; Cardiomyopathies - diagnosis; Decorin - blood; Decorin - genetics; Diagnosis, Differential; Female; Heart Failure - blood; Heart Failure - diagnosis; Heart Failure - physiopathology; Humans; Iduronidase - blood; Iduronidase - genetics; Male; Middle Aged; Original; Predictive Value of Tests; Reproducibility of Results; Stroke Volume; Ventricular Function, Left
• ISSN: 0008-6363; 1755-3245; 1755-3245
• DOI: 10.1093/cvr/cvae189

Abstract Aims Wild-type transthyretin cardiac amyloidosis (ATTRwt-CM) is an under-recognized aetiology of heart failure (HF), necessitating early detection for timely treatment. Our study aimed to differentiate patients with ATTRwt-CM from ATTRwt-negative HFpEF/HFmrEF patients by identifying and validating circulating protein biomarkers. In addition, we measured the same biomarkers in patients with cardiomyopathy due to light chain amyloidosis (AL)-CM to gain disease-specific insights. Methods and results In this observational study, serum concentrations of 363 protein biomarkers were measured in a discovery cohort consisting of 73 ATTRwt-CM, 55 AL-CM, and 59 ATTRwt-negative HFpEF/HFmrEF patients, using multiplex proximity extension assays. Sparse partial least squares analyses showed overlapping ATTRwt-CM and AL-CM biomarker profiles with clear visual differentiation from ATTRwt-negative patients. Pathway analyses with g:Profiler revealed significantly up-regulated proteoglycans (PG) and cell adhesion pathways in both ATTRwt-CM and AL-CM. Penalized regression analysis revealed that the proteoglycan decorin (DCN), lysosomal hydrolase alpha-L-iduronidase (IDUA) and glycosyl hydrolase galactosidase β-1 (GLB-1) most effectively distinguished ATTRwt-CM from ATTRwt-negative patients (R2 = 0.71). In a prospective validation cohort of 35 ATTRwt-CM patients and 25 ATTRwt-negative patients, DCN and IDUA significantly predicted ATTRwt-CM in the initial analysis (DCN: OR 3.3, IDUA: OR 0.4). While DCN remained significant after correcting for echocardiographic parameters, IDUA did not. DCN showed moderate discriminative ability (AUC, 0.74; 95% CI, 0.61–0.87; sensitivity, 0.91; specificity, 0.52) as did IDUA (AUC, 0.78; 95% CI, 0.65–0.91; sensitivity, 0.91; specificity, 0.61). A model combining clinical factors (AUC 0.92) outperformed DCN but not IDUA, a combination of the biomarkers was not significantly better. Neither DCN nor IDUA correlated with established disease markers. Conclusion ATTRwt-CM has a distinctly different biomarker profile compared with HFpEF/HFmrEF, while ATTRwt-CM patients share a similar biomarker profile with AL-CM patients characterized by up-regulation of proteoglycans and cell-adhesion pathways. The biomarkers DCN and IDUA show the potential to serve as an initial screening tool for ATTTRwt-CM. Further research is needed to determine the clinical usefulness of these and other extracellular matrix components in identifying ATTRwt-CM. Graphical