Author + information
- Received June 15, 2017
- Revision received September 18, 2017
- Accepted September 21, 2017
- Published online January 7, 2019.
- Anvesha Singh, MBChB, PhDa,∗ (, )
- Daniel C.S. Chan, BMedSci, BMBSa,
- John P. Greenwood, MBChB, PhDb,
- Dana K. Dawson, DM, PhDc,
- Piotr Sonecki, MDd,
- Kai Hogrefe, MDe,
- Damian J. Kelly, MBChB, MDf,
- Vijay Dhakshinamurthy, MBBSg,
- Chim C. Lang, MBChB, MDh,
- Jeffery P. Khoo, MBChB, PhDi,
- David Sprigings, MBChBj,
- Richard P. Steeds, MBBS, MDk,
- Ruiqi Zhang, PhDl,
- Ian Ford, PhDl,
- Michael Jerosch-Herold, PhDm,
- Jing Yang, PhDn,
- Zhuyin Li, PhDn,
- Leong L. Ng, MB Bchir, MDa and
- Gerry P. McCann, MBChB, MDa
- aDepartment of Cardiovascular Sciences, University of Leicester and the NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Leicester, United Kingdom
- bMultidisciplinary Cardiovascular Research Centre & The Division of Biomedical Imaging, Leeds Institute of Cardiovascular & Metabolic Medicine, Leeds University, Leeds, United Kingdom
- cCardiovascular Medicine Research Unit, School of Medicine and Dentistry, University of Aberdeen, Foresterhill, Aberdeen, United Kingdom
- dBHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
- eCardiology Department, Kettering General Hospital Foundation Trust, Kettering, United Kingdom
- fCardiology Department, Royal Derby Hospital, Derby, United Kingdom
- gCardiology Department, University Hospital, Coventry, United Kingdom
- hDivision of Molecular and Clinical Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom
- iCardiology Department, Glenfield Hospital, Leicester, United Kingdom
- jNorthampton General Hospital, Cliftonville, Northampton, United Kingdom
- kInstitute for Cardiovascular Sciences, University of Birmingham, Department of Cardiology, Queen Elizabeth Hospital, Birmingham, United Kingdom
- lRoberston Centre for Bisotatistics, University of Glasgow, Glasgow, United Kingdom
- mBrigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts
- nBristol-Myers Squibb Company, Princeton, New Jersey
- ↵∗Address for correspondence:
Dr. Anvesha Singh, Glenfield Hospital, Groby Road, Leicester LE3 9QP, United Kingdom.
Objectives The aim of this study was to establish sex differences in remodeling and outcome in aortic stenosis (AS) and their associations with biomarkers of myocardial fibrosis.
Background The remodeling response and timing of symptoms is highly variable in AS, and sex plays an important role.
Methods A total of 174 patients (133 men, mean age 66.2 ± 13.3 years) with asymptomatic moderate to severe AS underwent comprehensive stress cardiac magnetic resonance imaging, transthoracic echocardiography, and biomarker analysis (matrix metalloproteinase [MMP]-2, -3, -7, -8, and -9; tissue inhibitor matrix metalloproteinases-1 and -4; syndecan-1 and -4; and N-terminal pro–B-type natriuretic peptide), and were followed up at 6-month intervals. A primary endpoint was a composite of typical AS symptoms necessitating referral for aortic valve replacement, cardiovascular death, or major adverse cardiovascular events.
Results For a similar severity of AS, male patients demonstrated higher indexed left ventricular (LV) volumes and mass, more concentric remodeling (higher LV mass/volume), a trend to more late gadolinium enhancement (present in 51.1% men vs. 34.1% women; p = 0.057), and higher extracellular volume index than female patients (13.27 [interquartile range (IQR): 11.5 to 17.0] vs. 11.53 [IQR: 10.5 to 13.5] ml/m2, p = 0.017), with worse systolic and diastolic function and higher MMP-3 and syndecan-4 levels, whereas female patients had higher septal E/e′. Male sex was independently associated with indexed LV mass (β = 13.32 [IQR: 9.59 to 17.05]; p < 0.001). During median follow-up of 374 (IQR: 351 to 498) days, a primary outcome, driven by spontaneous symptom onset, occurred in 21.8% of male and 43.9% of female patients (relative risk: 0.50 [95% confidence interval: 0.31 to 0.80]; p = 0.004). Measures of AS severity were associated with the primary outcome in both sexes, whereas N-terminal pro–B-type natriuretic peptide, MMP-3, and mass/volume were only associated in men.
Conclusions In AS, women tolerate pressure overload with less concentric remodeling and myocardial fibrosis but are more likely to develop symptoms. This may be related to higher wall stress and filling pressures in women.
This study was funded by the National Institute for Health Research (NIHR-PDF 2011-04-51 GPM). The views expressed are those of the authors and not of the NHS, NIHR, or the Department of Health. Dr. Singh was funded by the NIHR Leicester Cardiovascular Biomedical Research Unit. NIHR Comprehensive Local Research Networks and the Leeds and Leicester NIHR Clinical Research Facilities provided further support. Dr. Chan is funded by the British Heart Foundation (FS/15/10/31223). The Luminex assays were funded and performed by Bristol-Myers-Squibb, Princeton, New Jersey. Drs. Yang and Zi are employees of the Bristol-Myers-Squibb company. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Received June 15, 2017.
- Revision received September 18, 2017.
- Accepted September 21, 2017.
- 2019 American College of Cardiology Foundation