Symptom Onset in Aortic Stenosis - Relation to Sex Differences in Left Ventricular Remodelling

Anvesha Singh (Lead / Corresponding author), Daniel C. S. Chan, John P. Greenwood, Dana Dawson, Piotr Sonecki, Kai Hogrefe, Damian J. Kelly, Vijay Dhakshinamurthy, Chim Lang, Jeffery P. Khoo, David Sprigings, Richard P. Steeds, Ruiqi Zhang, Ian Ford, Michael Jerosch-Herold, Jing Yang, Zhuyin Li, Leong L. Ng, Gerry P. McCann

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Abstract

Objectives: To establish sex differences in remodelling and outcome in aortic stenosis (AS) and their associations with biomarkers of myocardial fibrosis.

Background: The remodelling response and timing of symptoms is highly variable in AS, and gender plays an important role.

Methods: 174 patients (133 male, mean age 66.2 ± 13.3 years) with asymptomatic moderate to severe AS underwent comprehensive stress cardiac magnetic resonance (CMR) imaging, trans-thoracic echocardiography (TTE) and biomarker analysis (MMP-2, 3, 7, 8 and 9, TIMP-1, 4, syndecan-1 and 4 and NT-proBNP), and were followed up at 6 monthly intervals. A primary endpoint was a composite of typical AS symptoms necessitating referral for AVR, cardiovascular death or major adverse cardiovascular events.

Results: For a similar severity of AS, male patients demonstrated higher indexed LV volumes and mass, more concentric remodelling (higher LV mass/volume), a trend to more late gadolinium enhancement (LGE) (present in 51.1% male vs. 34.1% female, p=0.057) and higher extra-cellular volume index than female patients (13.27 [11.5, 17.0] vs. 11.53 [10.5, 13.5] ml/m2, p=0.017), with worse systolic and diastolic function and higher MMP-3 and syndecan-4 levels, whilst females had higher septal E/e’. Male sex was independently associated with indexed LV mass (β=13.32 (9.59-17.05), p<0.001). During median follow-up of 374 (IQR 351-498) days, a primary outcome, driven by spontaneous symptom onset, occurred in 21.8% of male and 43.9% of female patients (RR 0.50 (CI 0.31, 0.80), p=0.004). Measures of AS severity were associated with the primary outcome in both sexes, whereas NT-proBNP, MMP3 and mass/volume were only associated in males.
Conclusions: In AS, females tolerate pressure overload with less concentric remodelling and myocardial fibrosis but are more likely to develop symptoms. This may be related to higher wall stress and filling pressures in females.
Original languageEnglish
JournalJACC. Cardiovascular Imaging
Early online date13 Dec 2017
DOIs
Publication statusE-pub ahead of print - 13 Dec 2017

Fingerprint

Ventricular Remodeling
Aortic Valve Stenosis
Sex Characteristics
Syndecan-4
Matrix Metalloproteinases
Fibrosis
Biomarkers
Syndecan-1
Pressure
Tissue Inhibitor of Metalloproteinase-1
Gadolinium
Echocardiography
Thorax
Referral and Consultation
Magnetic Resonance Imaging

Keywords

  • aortic stenosis
  • sex
  • remodelling
  • biomarkers

Cite this

Singh, A., Chan, D. C. S., Greenwood, J. P., Dawson, D., Sonecki, P., Hogrefe, K., ... McCann, G. P. (2017). Symptom Onset in Aortic Stenosis - Relation to Sex Differences in Left Ventricular Remodelling. JACC. Cardiovascular Imaging. https://doi.org/10.1016/j.jcmg.2017.09.019
Singh, Anvesha ; Chan, Daniel C. S. ; Greenwood, John P. ; Dawson, Dana ; Sonecki, Piotr ; Hogrefe, Kai ; Kelly, Damian J. ; Dhakshinamurthy, Vijay ; Lang, Chim ; Khoo, Jeffery P. ; Sprigings, David ; Steeds, Richard P. ; Zhang, Ruiqi ; Ford, Ian ; Jerosch-Herold, Michael ; Yang, Jing ; Li, Zhuyin ; Ng, Leong L. ; McCann, Gerry P. / Symptom Onset in Aortic Stenosis - Relation to Sex Differences in Left Ventricular Remodelling. In: JACC. Cardiovascular Imaging. 2017.
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title = "Symptom Onset in Aortic Stenosis - Relation to Sex Differences in Left Ventricular Remodelling",
abstract = "Objectives: To establish sex differences in remodelling and outcome in aortic stenosis (AS) and their associations with biomarkers of myocardial fibrosis.Background: The remodelling response and timing of symptoms is highly variable in AS, and gender plays an important role.Methods: 174 patients (133 male, mean age 66.2 ± 13.3 years) with asymptomatic moderate to severe AS underwent comprehensive stress cardiac magnetic resonance (CMR) imaging, trans-thoracic echocardiography (TTE) and biomarker analysis (MMP-2, 3, 7, 8 and 9, TIMP-1, 4, syndecan-1 and 4 and NT-proBNP), and were followed up at 6 monthly intervals. A primary endpoint was a composite of typical AS symptoms necessitating referral for AVR, cardiovascular death or major adverse cardiovascular events.Results: For a similar severity of AS, male patients demonstrated higher indexed LV volumes and mass, more concentric remodelling (higher LV mass/volume), a trend to more late gadolinium enhancement (LGE) (present in 51.1{\%} male vs. 34.1{\%} female, p=0.057) and higher extra-cellular volume index than female patients (13.27 [11.5, 17.0] vs. 11.53 [10.5, 13.5] ml/m2, p=0.017), with worse systolic and diastolic function and higher MMP-3 and syndecan-4 levels, whilst females had higher septal E/e’. Male sex was independently associated with indexed LV mass (β=13.32 (9.59-17.05), p<0.001). During median follow-up of 374 (IQR 351-498) days, a primary outcome, driven by spontaneous symptom onset, occurred in 21.8{\%} of male and 43.9{\%} of female patients (RR 0.50 (CI 0.31, 0.80), p=0.004). Measures of AS severity were associated with the primary outcome in both sexes, whereas NT-proBNP, MMP3 and mass/volume were only associated in males.Conclusions: In AS, females tolerate pressure overload with less concentric remodelling and myocardial fibrosis but are more likely to develop symptoms. This may be related to higher wall stress and filling pressures in females.",
keywords = "aortic stenosis, sex, remodelling, biomarkers",
author = "Anvesha Singh and Chan, {Daniel C. S.} and Greenwood, {John P.} and Dana Dawson and Piotr Sonecki and Kai Hogrefe and Kelly, {Damian J.} and Vijay Dhakshinamurthy and Chim Lang and Khoo, {Jeffery P.} and David Sprigings and Steeds, {Richard P.} and Ruiqi Zhang and Ian Ford and Michael Jerosch-Herold and Jing Yang and Zhuyin Li and Ng, {Leong L.} and McCann, {Gerry P.}",
note = "Funding: National Institute for Health Research (NIHR-PDF 2011-04-51 GPM); British Heart Foundation(FS/15/10/31223).",
year = "2017",
month = "12",
day = "13",
doi = "10.1016/j.jcmg.2017.09.019",
language = "English",
journal = "JACC. Cardiovascular Imaging",
issn = "1936-878X",
publisher = "Elsevier",

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Singh, A, Chan, DCS, Greenwood, JP, Dawson, D, Sonecki, P, Hogrefe, K, Kelly, DJ, Dhakshinamurthy, V, Lang, C, Khoo, JP, Sprigings, D, Steeds, RP, Zhang, R, Ford, I, Jerosch-Herold, M, Yang, J, Li, Z, Ng, LL & McCann, GP 2017, 'Symptom Onset in Aortic Stenosis - Relation to Sex Differences in Left Ventricular Remodelling', JACC. Cardiovascular Imaging. https://doi.org/10.1016/j.jcmg.2017.09.019

Symptom Onset in Aortic Stenosis - Relation to Sex Differences in Left Ventricular Remodelling. / Singh, Anvesha (Lead / Corresponding author); Chan, Daniel C. S.; Greenwood, John P.; Dawson, Dana; Sonecki, Piotr; Hogrefe, Kai; Kelly, Damian J.; Dhakshinamurthy, Vijay; Lang, Chim; Khoo, Jeffery P.; Sprigings, David; Steeds, Richard P.; Zhang, Ruiqi; Ford, Ian; Jerosch-Herold, Michael; Yang, Jing; Li, Zhuyin; Ng, Leong L.; McCann, Gerry P.

In: JACC. Cardiovascular Imaging, 13.12.2017.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Symptom Onset in Aortic Stenosis - Relation to Sex Differences in Left Ventricular Remodelling

AU - Singh, Anvesha

AU - Chan, Daniel C. S.

AU - Greenwood, John P.

AU - Dawson, Dana

AU - Sonecki, Piotr

AU - Hogrefe, Kai

AU - Kelly, Damian J.

AU - Dhakshinamurthy, Vijay

AU - Lang, Chim

AU - Khoo, Jeffery P.

AU - Sprigings, David

AU - Steeds, Richard P.

AU - Zhang, Ruiqi

AU - Ford, Ian

AU - Jerosch-Herold, Michael

AU - Yang, Jing

AU - Li, Zhuyin

AU - Ng, Leong L.

AU - McCann, Gerry P.

N1 - Funding: National Institute for Health Research (NIHR-PDF 2011-04-51 GPM); British Heart Foundation(FS/15/10/31223).

PY - 2017/12/13

Y1 - 2017/12/13

N2 - Objectives: To establish sex differences in remodelling and outcome in aortic stenosis (AS) and their associations with biomarkers of myocardial fibrosis.Background: The remodelling response and timing of symptoms is highly variable in AS, and gender plays an important role.Methods: 174 patients (133 male, mean age 66.2 ± 13.3 years) with asymptomatic moderate to severe AS underwent comprehensive stress cardiac magnetic resonance (CMR) imaging, trans-thoracic echocardiography (TTE) and biomarker analysis (MMP-2, 3, 7, 8 and 9, TIMP-1, 4, syndecan-1 and 4 and NT-proBNP), and were followed up at 6 monthly intervals. A primary endpoint was a composite of typical AS symptoms necessitating referral for AVR, cardiovascular death or major adverse cardiovascular events.Results: For a similar severity of AS, male patients demonstrated higher indexed LV volumes and mass, more concentric remodelling (higher LV mass/volume), a trend to more late gadolinium enhancement (LGE) (present in 51.1% male vs. 34.1% female, p=0.057) and higher extra-cellular volume index than female patients (13.27 [11.5, 17.0] vs. 11.53 [10.5, 13.5] ml/m2, p=0.017), with worse systolic and diastolic function and higher MMP-3 and syndecan-4 levels, whilst females had higher septal E/e’. Male sex was independently associated with indexed LV mass (β=13.32 (9.59-17.05), p<0.001). During median follow-up of 374 (IQR 351-498) days, a primary outcome, driven by spontaneous symptom onset, occurred in 21.8% of male and 43.9% of female patients (RR 0.50 (CI 0.31, 0.80), p=0.004). Measures of AS severity were associated with the primary outcome in both sexes, whereas NT-proBNP, MMP3 and mass/volume were only associated in males.Conclusions: In AS, females tolerate pressure overload with less concentric remodelling and myocardial fibrosis but are more likely to develop symptoms. This may be related to higher wall stress and filling pressures in females.

AB - Objectives: To establish sex differences in remodelling and outcome in aortic stenosis (AS) and their associations with biomarkers of myocardial fibrosis.Background: The remodelling response and timing of symptoms is highly variable in AS, and gender plays an important role.Methods: 174 patients (133 male, mean age 66.2 ± 13.3 years) with asymptomatic moderate to severe AS underwent comprehensive stress cardiac magnetic resonance (CMR) imaging, trans-thoracic echocardiography (TTE) and biomarker analysis (MMP-2, 3, 7, 8 and 9, TIMP-1, 4, syndecan-1 and 4 and NT-proBNP), and were followed up at 6 monthly intervals. A primary endpoint was a composite of typical AS symptoms necessitating referral for AVR, cardiovascular death or major adverse cardiovascular events.Results: For a similar severity of AS, male patients demonstrated higher indexed LV volumes and mass, more concentric remodelling (higher LV mass/volume), a trend to more late gadolinium enhancement (LGE) (present in 51.1% male vs. 34.1% female, p=0.057) and higher extra-cellular volume index than female patients (13.27 [11.5, 17.0] vs. 11.53 [10.5, 13.5] ml/m2, p=0.017), with worse systolic and diastolic function and higher MMP-3 and syndecan-4 levels, whilst females had higher septal E/e’. Male sex was independently associated with indexed LV mass (β=13.32 (9.59-17.05), p<0.001). During median follow-up of 374 (IQR 351-498) days, a primary outcome, driven by spontaneous symptom onset, occurred in 21.8% of male and 43.9% of female patients (RR 0.50 (CI 0.31, 0.80), p=0.004). Measures of AS severity were associated with the primary outcome in both sexes, whereas NT-proBNP, MMP3 and mass/volume were only associated in males.Conclusions: In AS, females tolerate pressure overload with less concentric remodelling and myocardial fibrosis but are more likely to develop symptoms. This may be related to higher wall stress and filling pressures in females.

KW - aortic stenosis

KW - sex

KW - remodelling

KW - biomarkers

U2 - 10.1016/j.jcmg.2017.09.019

DO - 10.1016/j.jcmg.2017.09.019

M3 - Article

JO - JACC. Cardiovascular Imaging

JF - JACC. Cardiovascular Imaging

SN - 1936-878X

ER -