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Original research
Novel predictive role for mid-regional proadrenomedullin in moderate to severe aortic stenosis
  1. Eugene S J Tan1,2,
  2. Yen Yee Oon1,3,
  3. Siew Pang Chan2,
  4. Oi Wah Liew2,4,
  5. Jenny P C Chong2,4,
  6. Edgar Tay1,5,
  7. Wern Miin Soo1,
  8. James W L Yip1,2,
  9. Lingli Gong2,
  10. Josephine B Lunaria2,
  11. Quek Wei Yong6,
  12. Evelyn Min Lee6,
  13. Daniel P S Yeo6,7,
  14. Zee Pin Ding8,
  15. Hak Chiaw Tang8,
  16. See Hooi Ewe8,
  17. Calvin C W Chin8,
  18. Siang Chew Chai9,
  19. Ping Ping Goh5,
  20. Lee Fong Ling10,
  21. Hean Yee Ong10,
  22. A Mark Richards1,2,4,11,
  23. Lieng Hsi Ling1,2,4
  1. 1 Department of Cardiology, National University Heart Centre, Singapore
  2. 2 Yong Loo Lin School of Medicine, National University Singapore, Singapore
  3. 3 Department of Cardiology, Sarawak Heart Center, Sarawak, Malaysia
  4. 4 Cardiovascular Research Institute, National University Heart Centre, Singapore
  5. 5 Asian Heart & Vascular Centre, Mount Elizabeth Novena Hospital, Singapore
  6. 6 Department of Cardiology, Tan Tock Seng Hospital, Singapore
  7. 7 Apex Heart Clinic, Gleneagles Hospital, Singapore
  8. 8 Department of Cardiology, National Heart Centre, Singapore
  9. 9 Department of Cardiology, Changi General Hospital, Singapore
  10. 10 Department of Cardiology, Khoo Teck Puat Hospital, Singapore
  11. 11 Christchurch Heart Institute, University of Otago, Dunedin, New Zealand
  1. Correspondence to Dr Lieng Hsi Ling, Cardiology, National University Heart Centre, Singapore 119074, Singapore; mdcllh{at}


Objective We investigated the prognostic significance of selected known and novel circulating biomarkers in aortic stenosis (AS).

Methods N-terminal pro-BNP (NT-proBNP), high-sensitivity troponin-T (hsTnT), growth differentiation factor-15 (GDF-15), suppression of tumorigenicity-2 (ST2), mid-regional proadrenomedullin (MR-proADM) and mid-regional proatrial natriuretic peptide (MR-proANP) were measured in patients with moderate to severe AS, New York Heart Association (NYHA) class I-II and left ventricular ejection fraction ≥50%, recruited consecutively across five centres from 2011 to 2018. Their ability to predict both primary (all-cause mortality, heart failure hospitalisation or progression to NYHA class III-IV) and secondary (additionally incorporating syncope and acute coronary syndrome) outcomes was determined by competing risk analyses.

Results Among 173 patients with AS (age 69±11 years, 55% male, peak transaortic velocity (Vmax) 4.0±0.8 m/s), the primary and secondary outcomes occurred in 59 (34%) and 66 (38%), respectively. With aortic valve replacement as a competing risk, the primary outcome was determined consistently by the comorbidity index and each selected biomarker except ST2 (p<0.05), independent of NYHA class, Vmax, LV-global longitudinal strain and serum creatinine. MR-proADM had the highest discriminative value for both primary (subdistribution HR (SHR) 11.3, 95% CI 3.9 to 32.7) and secondary outcomes (SHR 12.6, 95% CI 4.7 to 33.5). Prognostic assessment of dual-biomarker combinations identified MR-proADM plus either hsTnT or NT-proBNP as the best predictive model for both clinical outcomes. Paired biomarker models were not superior to those including MR-proADM as the sole circulating biomarker.

Conclusion MR-proADM most powerfully portended worse prognosis and should be further assessed as possibly the biomarker of choice for risk stratification in AS.

  • Aortic stenosis
  • Biomarkers

Data availability statement

Data are available on reasonable request.

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Data availability statement

Data are available on reasonable request.

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  • ESJT and YYO are joint first authors.

  • ESJT and YYO contributed equally.

  • Correction notice This article has been corrected since it was first published. The number of cardiovascular deaths reported in the Clinical outcomes section of the Results has been corrected from 18 to 14.

  • Contributors ESJT was involved in conception, analysis and interpretation of data and drafting of the manuscript. S-PC was involved in the analysis and interpretation of data. OWL, JPCC, ET, WMS, JWLY, LG, JBL, QWY, EML, DPSY, ZPD, HCT, SHE, CWLC, SCC, PPG, LFL and HYO were involved in the critical revision of the manuscript. AMR and LHL were involved in the conception, analysis and interpretation of data and critical revision of the manuscript. LHL is the guarantor and accepts full responsibility for the finished work and/or the conduct of the study, had access to the data, and controlled the decision to publish.

  • Funding This study was funded by the National Medical Research Council, Singapore (NMRC/CG/NUHCS/2010, NMRC/CG12Aug14, NMRC/CGAug16C006).

  • Competing interests SHE reports personal fees from Medtronic, Edwards Lifesciences and Abbott Medical, outside the submitted work. ZPD reports personal/speaker fees from GE and Phillips, and non-financial support from Phillips, outside the submitted work. AMR reports grants from National Medical Research Council of Singapore during the conduct of the study, is a long-term collaborator with Roche Diagnostics, the provider of assays central to this submission, and received support in kind, grants, speaker’s honoraria and acted on advisory boards for Roche Diagnostics. LHHL reports grants from National Medical Research Council of Singapore during the conduct of the study.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

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

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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