Abstract 598 Proteomics for Phenotyping and Risk Stratification in Heart Failure with Preserved Ejection Fraction and Obesity

Background:

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome without effective therapies. Reducing the heterogeneity by studying clinical HFpEF subtypes might enable the development of targeted therapies. An obesity associated HFpEF phenotype has been suggested and shown to be related to a poor clinical course. However, pathophysiological factors contributing to this phenotype remain elusive.

We therefore sought to investigate whether the HFpEF obese phenotype is reflected by distinct circulating proteome biomarkers.

Methods and Results:

Among 6995 patients from the LIFE Heart study, we selected 999 patients with HFpEF, according to the 2016 European Society of Cardiology definition, and 999 patients without heart failure (no-HF). Overall, 92 circulating serum biomarkers were measured using a proximity extension assay.

HFpEF patients were older, demonstrated higher NT-pro-BNP levels, inflammatory markers and more comorbidities including coronary artery disease, hypertension and type 2 diabetes as compared to no-HF patients (p<0.05 for all). After Bonferroni correction, Adrenomedullin (ADM), Galectin-9 (Gal-9), Thrombospondin-2 (THBS-2) and CD4 were significantly elevated in obese HFpEF (Body mass index [BMI] >=30 kg/m², n=464) patients when compared to lean HFpEF (BMI <30 kg/m², n=535) and obese no-HF patients (BMI >=30 kg/m², n=387) (p<0.00001). Higher concentrations of these four proteins were associated with higher markers of HFpEF severity (HFA-PEFF score, E/E’, estimated pulmonary pressure and NT-proBNP) as well as inflammation (CRP) (p<0.05 for all). Importantly, ADM, Gal-9 and CD4 were associated with increased mortality in all symptomatic HFpEF patients as well as the symptomatic obese HFpEF subgroup.

Conclusion:

Obese HFpEF patients exhibit higher circulating biomarkers of volume expansion (ADM), myocardial fibrosis (THBS-2) and systemic inflammation (Gal-9, CD4) compared to obese non-HFpEF or lean HFpEF. These findings have the potential to support the diagnosis, monitor diseases state, improve the prediction of the disease courses and may define future treatment targets in patients with HFpEF and obesity.

Central Illustration:

Clin Res Cardiol (2021) DOI DOI https://doi.org/10.1007/s00392-021-01843-w
Proteomics for Phenotyping and Risk Stratification in Heart Failure with Preserved Ejection Fraction and Obesity
K.-P. Rommel¹, K.-P. Kresoja¹, C. Besler¹, S. Henger², N. Klöting³, P. Büttner¹, U. Ceglarek⁴, H. Thiele¹, M. Scholz², M. Blüher³, P. Lurz¹
¹Klinik für Innere Medizin/Kardiologie, Herzzentrum Leipzig - Universität Leipzig, Leipzig; ²Institut für Medizinische Informatik, Statistik und Epidemiologie (IMISE), Universität Leipzig, Leipzig; ³Klinik und Poliklinik für Endokrinologie, Nephrologie, Rheumatologie, Universitätklinikum Leipzig, Leipzig; ⁴Institut für Laboratoriumsmedizin, Klinische Chemie und Molekulare Diagnostik, Universitätsklinikum Leipzig, Leipzig;
Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome without effective therapies. Reducing the heterogeneity by studying clinical HFpEF subtypes might enable the development of targeted therapies. An obesity associated HFpEF phenotype has been suggested and shown to be related to a poor clinical course. However, pathophysiological factors contributing to this phenotype remain elusive. We therefore sought to investigate whether the HFpEF obese phenotype is reflected by distinct circulating proteome biomarkers. Methods and Results: Among 6995 patients from the LIFE Heart study, we selected 999 patients with HFpEF, according to the 2016 European Society of Cardiology definition, and 999 patients without heart failure (no-HF). Overall, 92 circulating serum biomarkers were measured using a proximity extension assay. HFpEF patients were older, demonstrated higher NT-pro-BNP levels, inflammatory markers and more comorbidities including coronary artery disease, hypertension and type 2 diabetes as compared to no-HF patients (p<0.05 for all). After Bonferroni correction, Adrenomedullin (ADM), Galectin-9 (Gal-9), Thrombospondin-2 (THBS-2) and CD4 were significantly elevated in obese HFpEF (Body mass index [BMI] >=30 kg/m², n=464) patients when compared to lean HFpEF (BMI <30 kg/m², n=535) and obese no-HF patients (BMI >=30 kg/m², n=387) (p<0.00001). Higher concentrations of these four proteins were associated with higher markers of HFpEF severity (HFA-PEFF score, E/E’, estimated pulmonary pressure and NT-proBNP) as well as inflammation (CRP) (p<0.05 for all). Importantly, ADM, Gal-9 and CD4 were associated with increased mortality in all symptomatic HFpEF patients as well as the symptomatic obese HFpEF subgroup. Conclusion: Obese HFpEF patients exhibit higher circulating biomarkers of volume expansion (ADM), myocardial fibrosis (THBS-2) and systemic inflammation (Gal-9, CD4) compared to obese non-HFpEF or lean HFpEF. These findings have the potential to support the diagnosis, monitor diseases state, improve the prediction of the disease courses and may define future treatment targets in patients with HFpEF and obesity. Central Illustration:
https://dgk.org/kongress_programme/jt2021/aP1428.html