Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort

Masatake Kobayashi; João Pedro Ferreira; Duarte Kevin; Emmanuel Bresso; Olivier Huttin; Erwan Bozec; Hans-Peter Brunner La Rocca; Christian Delles; Andrew L Clark; Frank Edelmann; Arantxa González; Stephane Heymans; Pierpaolo Pellicori; Johannes Petutschnigg; Job A J Verdonschot; Patrick Rossignol; John G F Cleland; Faiez Zannad; Nicolas Girerd; on behalf of the HOMAGE Trial Committees and Investigators

doi:10.1002/ejhf.3202

Proteomic profiles of left atrial volume and its influence on response to spironolactone: Findings from the HOMAGE trial and STANISLAS cohort

Eur J Heart Fail. 2024 Mar 25. doi: 10.1002/ejhf.3202. Online ahead of print.

Authors

Masatake Kobayashi^{1

2}, João Pedro Ferreira^{1

3}, Duarte Kevin¹, Emmanuel Bresso¹, Olivier Huttin¹, Erwan Bozec¹, Hans-Peter Brunner La Rocca⁴, Christian Delles⁵, Andrew L Clark⁶, Frank Edelmann⁷, Arantxa González^{8

9}, Stephane Heymans⁴, Pierpaolo Pellicori⁵, Johannes Petutschnigg¹⁰, Job A J Verdonschot⁴, Patrick Rossignol^{1

11}, John G F Cleland⁵, Faiez Zannad¹, Nicolas Girerd¹; on behalf of the HOMAGE Trial Committees and Investigators

Affiliations

¹ Université de Lorraine, INSERM, Centre d'Investigations Cliniques Plurithématique 1433, Inserm U1116, CHRU de Nancy and F-CRIN INI-CRCT, Nancy, France.
² Department of Cardiology, Tokyo Medical University Hospital, Tokyo, Japan.
³ Cardiovascular Research and Development Center, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal.
⁴ Department of Cardiology, Maastricht University Medical Center, Maastricht, The Netherlands.
⁵ School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK.
⁶ Department of Cardiology, University of Hull, Castle Hill Hospital, Yorkshire, UK.
⁷ Department of Internal Medicine and Cardiology Campus Virchow Klinikum, Charité University Medicine Berlin and German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
⁸ CIMA Universidad de Navarra, Department of Pathology, Anatomy and Physiology Universidad de Navarra and IdiSNA, Pamplona, Spain.
⁹ CIBERCV, Carlos III Institute of Health, Madrid, Spain.
¹⁰ Department of Internal Medicine and/Cardiology, Campus Virchow Klinikum, Charité University Medicine Berlin, and German Heart Center Berlin, and Berlin Institute of Health (BIH), and German Centre for Cardiovascular research (DZHK), Berlin, Germany.
¹¹ Medical Specialties and Nephrology Dialysis Departments, Monaco Princess Grace Hospital and Monaco Private Hemodialysis Centre, Monaco, Monaco.

PMID: 38528728
DOI: 10.1002/ejhf.3202

Abstract

Aims: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables.

Methods and results: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m²). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m²). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (p_interaction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (p_interaction > 0.10).

Conclusion: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.

Keywords: Biomarkers; Echocardiogram; Heart failure; Left atrial volume; Spironolactone.

Abstract

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