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Heart. 2018 Aug 18. pii: heartjnl-2018-313182. doi: 10.1136/heartjnl-2018-313182. [Epub ahead of print]

Potential spironolactone effects on collagen metabolism biomarkers in patients with uncontrolled blood pressure.

Ferreira JP1,2,3,4,5, Rossignol P1,2,3, Pizard A1,2,3, Machu JL1,2,3, Collier T6, Girerd N1,2,3, Huby AC1,2,3, Gonzalez A7,8, Diez J7,8,9, López B8, Sattar N10, Cleland JG11,12, Sever PS13, Zannad F1,2,3.

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Centre d'Investigations Cliniques Plurithématique Inserm 1433, Université de Lorraine, Nancy, France.
CHRU de Nancy, Inserm U1116, Université de Lorraine, Nancy, France.
FCRIN INI-CRCT, Université de Lorraine, Nancy, France.
Department of Physiology, University of Porto, Porto, Portugal.
Department of Cardiothoracic Surgery, University of Porto, Porto, Portugal.
Department of Medical Statistics, London School of Hygiene and Tropical Medicine, London, UK.
Program of Cardiovascular Diseases, CIMA, University of Navarra and Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
CIBERCV, Carlos III Institute of Health, Madrid, Spain.
Department of Cardiology and Cardiac Surgery, University of Navarra Clinic, Pamplona, Spain.
Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.
Robertson Centre for Biostatistics and Clinical Trials, University of Glasgow, Glasgow, UK.
National Heart and Lung Institute, Imperial College London, London, UK.
International Centre for Circulatory Health, Imperial College London, London, UK.



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).


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.


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.


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.


heart failure; hypertension

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Conflict of interest statement

Competing interests: None declared.

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