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Original research article
Potential spironolactone effects on collagen metabolism biomarkers in patients with uncontrolled blood pressure
  1. João Pedro Ferreira1,2,3,4,5,
  2. Patrick Rossignol1,2,3,
  3. Anne Pizard1,2,3,
  4. Jean-Loup Machu1,2,3,
  5. Timothy Collier6,
  6. Nicolas Girerd1,2,3,
  7. Anne-Cécile Huby1,2,3,
  8. Arantxa Gonzalez7,8,
  9. Javier Diez7,8,9,
  10. Begoña López8,
  11. Naveed Sattar10,
  12. John G Cleland11,12,
  13. Peter S Sever13,
  14. Faiez Zannad1,2,3
  1. 1 Centre d’Investigations Cliniques Plurithématique Inserm 1433, Université de Lorraine, Nancy, France
  2. 2 CHRU de Nancy, Inserm U1116, Université de Lorraine, Nancy, France
  3. 3 FCRIN INI-CRCT, Université de Lorraine, Nancy, France
  4. 4 Department of Physiology, University of Porto, Porto, Portugal
  5. 5 Department of Cardiothoracic Surgery, University of Porto, Porto, Portugal
  6. 6 Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK
  7. 7 Program of Cardiovascular Diseases, CIMA, University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain
  8. 8 CIBERCV, Carlos III Institute of Health, Madrid, Spain
  9. 9 Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain
  10. 10 Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
  11. 11 Robertson Centre for Biostatistics and Clinical Trials, University of Glasgow, Glasgow, UK
  12. 12 National Heart and Lung Institute, Imperial College London, London, UK
  13. 13 International Centre for Circulatory Health, Imperial College London, London, UK
  1. Correspondence to João Pedro Ferreira, Centre d’Investigation Clinique 1433 module Plurithématique, CHRU Nancy - Hopitaux de Brabois, Institut Lorrain du Coeur et des Vaisseaux Louis Mathieu, Nancy 54500, France; jp7ferreira{at}


Background An increase in myocardial collagen content may contribute to the development of heart failure; this might be inhibited or reversed by mineralocorticoid receptor antagonists (MRAs). We investigated changes in serum concentrations of the collagen synthesis biomarkers N-terminal propeptide of procollagen type III (PIIINP) (primary outcome) and C-terminal propeptide of procollagen type I (PICP) (secondary outcome) after non-randomised initiation of spironolactone as add-on therapy among patients with resistant hypertension enrolled in the ‘Anglo-Scandinavian Cardiac Outcomes’ trial (ASCOT).

Methods An age/sex matching plus propensity-scored logistic regression model incorporating variables related to the outcome and spironolactone treatment was created to compare patients treated with spironolactone for a 9-month period versus matched controls. A within-person analysis comparing changes in serum biomarker concentrations in the 9 months before versus after spironolactone treatment was also performed.

Results Patients included in the between-person analysis (n=146) were well matched: the mean age was 63±7 years and 11% were woman. Serum concentrations of PIIINP and PICP rose in ‘controls’ and fell during spironolactone treatment (adjusted means +0.52 (−0.05 to 1.09) vs −0.41 (−0.97 to 0.16) ng/mL, p=0.031 for PIIINP and +4.54(−1.77 to 10.9) vs −6.36 (−12.5 to −0.21) ng/mL, p=0.023 for PICP). For the within-person analysis (n=173), spironolactone treatment was also associated with a reduction in PICP (beta estimate=−11.82(−17.53 to −6.10) ng/mL, p<0.001) but not in PIIINP levels.

Conclusions Treatment with spironolactone was associated with a reduction in serum biomarkers of collagen synthesis independently of blood pressure in patients with hypertension, suggesting that spironolactone might exert favourable effects on myocardial collagen synthesis and fibrosis. Whether this effect might contribute to slowing the progression to heart failure is worth investigating.

  • hypertension
  • heart failure

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  • Funding This work is supported by the European Union: HEALTH-F7- 305507 HOMAGE (EU FP7 305507 The European Research Council Advanced Researcher Grant-2011-294713-EPLORE and the Fonds voor Wetenschappelijk Onderzoek Vlaanderen, Ministry of the Flemish Community, Brussels, Belgium (G.0881.13 and G.088013), currently support the Studies Coordinating Centre in Leuven. JF, PR and FZ are supported by a public grant overseen by the French National Research Agency (ANR) as part of the second ‘Investissements d’Avenir’ programme (Fighting Heart Failure reference: ANR-15-RHU-0004 and GEENAGE IMPACT Lorraine University Excellence).

  • Competing interests None declared.

  • Patient consent Obtained.

  • Ethics approval ASCOT trial.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement The data described in the present manuscript may be available upon request to the steering committee of the ASCOT trial.