The impact of menopausal hormone therapy (MHT) on cardiac structure and function: Insights from the UK Biobank imaging enhancement study
The impact of menopausal hormone therapy (MHT) on cardiac structure and function: Insights from the UK Biobank imaging enhancement study
Mihir M. Sanghvi 0 1
Nay Aung 0 1
Jackie A. Cooper 0 1
JoseÂ Miguel Paiva 0 1
Aaron M. Lee 0 1
Filip Zemrak 0 1
Kenneth Fung 0 1
Ross J. Thomson 0 1
Elena Lukaschuk 1
Valentina Carapella 1
Young Jin Kim 1
Nicholas C. Harvey 1
Stefan K. Piechnik 1
Stefan Neubauer 1
Steffen E. Petersen 0 1
0 William Harvey Research Institute, NIHR Biomedical Research Centre at Barts, Queen Mary University of London , Charterhouse Square, London , United Kingdom , 2 Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford , Oxford , United Kingdom , 3 Department of Radiology, Severance Hospital, Yonsei University College of Medicine , Seoul , South Korea , 4 MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton General Hospital , Southampton , United Kingdom , 5 NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust , Southampton , United Kingdom
1 Editor: N. Charlotte Onland-Moret, Universitair Medisch Centrum Utrecht , NETHERLANDS
Data Availability Statement: The data in this study
is owned by a third party, the UK Biobank (www.
ukbiobank.ac.uk) and legal constraints do not
permit public sharing of the data. The UK Biobank,
however, is open to all bona fide researchers from
the academic, charity, public, and commercial
sectors, both in the UK and internationally. Thus,
the data used in this manuscript can be easily and
directly accessed by applying through the UK
Biobank Access Management System (www.
ukbiobank.ac.uk/register-apply). The data used in
The effect of menopausal hormone therapy (MHT)±previously known as hormone replace
ment therapy±on cardiovascular health remains unclear and controversial. This
cross-sectional study examined the impact of MHT on left ventricular (LV) and left atrial (LA) structure
and function, alterations in which are markers of subclinical cardiovascular disease, in a
Post-menopausal women who had never used MHT and those who had used MHT
years participating in the UK Biobank who had undergone cardiovascular magnetic
resonance (CMR) imaging and free of known cardiovascular disease were included.
Multivariable linear regression was performed to examine the relationship between cardiac
parameters and MHT use
3 years. To explore whether MHT use on each of the cardiac outcomes differed by age, multivariable regression models were constructed with a crossproduct of age and MHT fitted as an interaction term.
Of 1604 post-menopausal women, 513 (32%) had used MHT
3 years. In the MHT cohort,
median age at menopause was 50 (IQR: 45±52) and median duration of MHT was 8 years.
In the non-MHT cohort, median age at menopause was 51 (IQR: 48±53). MHT use was associated with significantly lower LV end-diastolic volume (122.8 ml vs 119.8 ml, effect
this study was accessed via access application
2964. The authors did not have preferential access
to UK Biobank data.
Funding: This work was supported by the following
institutions: KF is supported by The Medical
College of Saint Bartholomew's Hospital Trust
independent registered charity that promotes and
advances medical and dental education and
research at Barts and The London School of
Medicine and Dentistry. AL and SEP acknowledge
support from the NIHR Cardiovascular Biomedical
Research Centre at Barts (www.whri.qmul.ac.uk)
and from the ªSmartHeartº Engineering and
Physical Sciences Research Council (www.epsrc.
ac.uk) program grant (EP/P001009/1). SN and SKP
are supported by the Oxford NIHR Biomedical
Research Centre (www.oxfordbrc.nihr.ac.uk) and
the Oxford British Heart Foundation Centre of
Research Excellence (http://www.cardioscience.ox.
project was enabled through access to the MRC
eMedLab Medical Bioinformatics infrastructure,
supported by the Medical Research Council (grant
number MR/L016311/1) (www.emedlab.ac.uk). NA
is supported by a Wellcome Trust Research
Training Fellowship (203553/Z/Z) (www.wellcome.
ac.uk). The authors SEP, SN and SKP acknowledge
the British Heart Foundation (www.bhf.org.uk) for
funding the manual analysis to create a
cardiovascular magnetic resonance imaging
reference standard for the UK Biobank imaging
resource in 5000 CMR scans (PG/14/89/31194).
The funders had no role in study design, data
collection and analysis, decision to publish, or
preparation of the manuscript.
Competing interests: SEP provides consultancy to
Circle Cardiovascular Imaging Inc., Calgary,
Canada. This does not alter our adherence to PLOS
ONE policies on sharing data and materials. The
other authors have declared that no competing
Abbreviations: BMI, body mass index; bSSFP,
balanced steady-state free precession; CMR,
cardiovascular magnetic resonance; CVD,
cardiovascular disease; HERS, Heart and Estrogen/
Progestin Replacement Study; LA, left atrium; LV,
left ventricle; MHT, menopausal hormone therapy;
WHI, Women's Health Initiative.
size = -2.4%, 95% CI: -4.2% to -0.5%; p = 0.013) and LA maximal volume (60.2 ml vs 57.5
ml, effect size = -4.5%, 95% CI: -7.8% to -1.0%; p = 0.012). There was no significant
difference in LV mass. MHT use significantly modified the effect between age and CMR
parameters; MHT users had greater decrements in LV end-diastolic volume, LV end-systolic
volume and LA maximal volume with advancing age.
MHT use was not associated with adverse, subclinical changes in cardiac structure and function. Indeed, significantly smaller LV and LA chamber volumes were observed which have been linked to favourable cardiovascular outcomes. These findings represent a novel approach to examining MHT's effect on the cardiovascular system.
The effect of menopausal hormone therapy (MHT), previously known as hormone
replacement therapy, on cardiovascular health in post-menopausal women remains controversial and
unclear. Extensive observational data had suggested MHT to be cardioprotective [1±3], leading
to MHT being routinely prescribed for both primary and secondary prevention of coronary
heart disease (CHD). However, subsequent data from the Women's Health Initiative (WHI)
and Heart and Estrogen/Progestin Replacement Study (HERS) studies cast doubt on the
beneficial cardiovascular effects of MHT [4±6]; this was reflected in learned societies' clinical
guidance concerning MHT's role in CHD prevention [
]. The most recent randomised trial data
on the subject arose from the Danish Osteoporosis Prevention Study [
], which indicated that
women taking MHT had a reduced risk of the composite endpoint of mortality, heart failure
and myocardial infarction but the study has been subject to criticism [
]. In more recent
work, again from the WHI, there was no difference in cardiovascular mortality in MHT users
compared to placebo, although the authors themselves state that cause-specific mortality data
should be interpreted ªcautiouslyº [
]. it has been suggested that commencement of MHT in
the perimenopausal transition or early menopause is not associated with increased risk of
CHD compared to when treatment is administered at a later stage. This is known as the ªtim
ing hypothesisº [
The UK Biobank is an ongoing, large-scale, population-based study designed to examine
determinants of health in middle and old age [
]. Besides extensive collection of health
questionnaire data, biological samples and physical measurements, it has incorporated
cardiovascular magnetic resonance (CMR) imaging±the gold standard for analysis of cardiac structure
and function±to provide detailed imaging phenotypes [
]. At present, there is a paucity of
data on the effects of MHT on left ventricular (LV) and left atrial (LA) volumes and function,
alterations in which are markers of subclinical cardiovascular disease and have prognostic
This cross-sectional study aims to examine the impact of MHT on left ventricular and left atrial structure and function, as assessed by CMR, in a large, population-based cohort.
The UK Biobank is a versatile scientific resource, in which questionnaire data, physical measurements and biological samples were collected from over 500,000 individuals aged 40±69
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between 2006 and 2010 registered with the UK National Health Service; the study protocol has
been described in detail previously [
]. Additionally, the UK Biobank imaging enhancement
study is ongoing with the aim of performing, in a single visit, brain, heart, whole body, carotid
artery, bone and joint imaging in 100,000 of the original 500,000 participants. Cardiovascular
magnetic resonance imaging (CMR) was selected as the modality of choice for heart imaging.
The study population presented here consists of 1604 individuals, a subset of the 5,065 individ
uals who underwent CMR examination as part of the pilot phase (April 2014 ±August 2015) of
the UK Biobank imaging enhancement. All participants provided written consent; UK
Biobank's scientific protocol and operational procedures were reviewed and approved by the
North West Multi-centre Research Ethics Committee in the UK . The research presented here was conducted under access application 2964 and was approved by the UK Biobank access committee.
Male participants (n = 2356), female participants not reporting having undergone menopause
(n = 693), participants reporting myocardial infarction, angina, heart failure, arrhythmias
(including atrial fibrillation), cardiomyopathy, stroke or peripheral vascular disease (n = 76),
and participants using MHT for < 3 years or with missing duration data (n = 246) were
excluded from the analysis leaving a study population of 1604.
CMR protocol and image analysis
The UK Biobank CMR protocol has been described in detail elsewhere . Briefly, all exami
nations were performed on a wide-bore 1.5 Tesla scanner (MAGNETOM Aera, Syngo
Platform VD13A, Siemens Healthcare, Erlangen, Germany). For cardiac function, long axis cines
and a complete short axis stack of balanced steady-state free precession (bSSFP) cines, covering
the left and right ventricle were acquired.
Analysis of the cardiac chambers for all CMR examinations was performed manually across
two core laboratories according to pre-approved standard operating procedures using cvi42
post-processing software (Version 5.1.1, Circle Cardiovascular Imaging Inc., Calgary, Canada)
by observers blinded to all exposures. LV papillary muscles were included in blood pool
volumes and excluded from LV mass. Detailed descriptions of analysis methodology, including
reference ranges, exemplar contours and intra- and inter-observer variability, have been
previously described [
]. The CMR parameters examined in this study were left ventricular
enddiastolic volume, end-systolic volume, stroke volume, ejection fraction and mass and left atrial
Hormone replacement therapy and menopause
To reliably assess the impact of MHT on cardiac structure and function, only women using
MHT for 3 years were included in the analysis. Data concerning MHT use was derived from
UK Biobank fields 3546 (age last used MHT) and 3536 (age started MHT). Duration of MHT
use was calculated by subtracting values in these two fields. Where women indicated that they
were still currently using MHT, age at the time of imaging visit was used to determine
duration. Duration of menopause was calculated by subtracting age at menopause (data field 3581)
from age at time of imaging visit. To assess the impact of the ªtiming hypothesisº, a timing
variable was created defined as age of menopause subtracted from age started MHT expressed in
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Descriptive statistics for continuous variables were presented as mean ± standard deviation or
median and interquartile range (IQR) whilst categorical variables were presented as number
(percentage). Differences in means were tested using unpaired t-test or Mann-Whitney-U test
and differences in percentages using chi-squared test. CMR parameters used as dependent
variables were LV end-diastolic volume, LV end-systolic volume, LV stroke volume, LV ejection
fraction, LV mass, and LA maximal volume. All dependent variables were assessed for
normality using histograms and quantile-quantile plots; natural logarithmic transformation was
performed for all dependent variables barring LV ejection fraction. For each dependent variable,
outliers were defined as measurements more than three interquartile ranges below the first
quartile or above the third quartile and removed from analysis. With respect to missing values,
the data presented is a complete case analysis.
To examine the impact of MHT use on cardiac structure and function, multivariable linear
regression models were fitted for each cardiac (dependent) variable. With our sample size, the
study has 80% power at the 5% significance level to detect a 0.15 standard deviation difference
in any of the continuous variables; this would be considered a small effect size [
included in the model (Model 1) were age, age at menopause, ethnicity, height, weight, systolic
blood pressure, diastolic blood pressure, smoking status, regular alcohol use, presence of raised
cholesterol, presence of diabetes, Townsend deprivation index and income. Height and weight
were included as covariates in the model rather than indexing the dependent variables, as the
use of ratios in regression analysis can lead to spurious results and misinterpretation [
The adjustment made ensured all variables in the model were appropriately adjusted for body composition. The variance inflation factor was calculated to test for multicollinearity. Where cardiac variables had been log-transformed, the beta coefficients were anti-logged and expressed as a percentage difference.
To determine whether the effect of MHT use on each of the cardiac outcomes differed by
age, multivariable regression models were constructed with a cross-product of age and MHT
fitted as an interaction term. Co-variates included: duration of MHT use fitted as thirds,
ethnicity, height, weight, systolic blood pressure, diastolic blood pressure, smoking status, regular
alcohol use, presence of raised cholesterol, presence of diabetes, Townsend deprivation index
and income (Model 2). Interactions were tested using age as a continuous variable. For ease of
interpretation we also fitted the interaction using tertile of age and presented effect sizes for
MHT use by tertile.
The effect of multiple testing was considered by determining false discovery rates using the
Benjamini±Yekutieli procedure in order to establish the proportion of the rejected hypotheses that are likely to be true positives.
In sensitivity analyses, to examine differences between the MHT use 3 years and no
MHT use groups on CMR parameters, propensity-score matching was used. Matching was
performed using all co-variates used in Model 1 at a one-to-one ratio. Differences between
MHT use 3 years and propensity-matched controls was assessed using paired t-test.
To examine the effect of missing data, multiple imputation by chained equations was used
to impute 20 complete datasets on which the analysis was repeated and the results pooled.
Predictive mean matching with five nearest neighbours was used for continuous variables and
logistic regression for binary variables. Plots were examined to assess convergence and
plausibility of estimates.
All statistical analyses were performed using R (version 3.3.2) .
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A total of 1,604 participants were included in this study, 513 post-menopausal women who had used MHT for 3 years and 1,091 post-menopausal women who had never used MHT; case selection is depicted in Fig 1. The mean number of outliers for CMR variables was 2 (range = 0±7).
Baseline characteristics for the study population, divided by never used MHT vs MHT
use 3 years, are presented in Table 1. The mean age (65.4±5.7 vs 61.3±6.4; P<0.0001) was
higher and the median age at menopause (50 [IQR = 45±52] vs 51 [IQR = 48±53]; p<0.0001)
was lower in the MHT cohort compared to the never used MHT cohort. For those using
MHT, the median number of years of MHT use was 8 (IQR = 5±11) and the mean age of
Fig 1. Case selection flowchart.
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commencement was 47.6±5.3. At the time of CMR examination, 15.2% (n = 78) were still on
treatment. There was no significant difference in socioeconomic status measures between
MHT users and non-users including Townsend deprivation index, household income or educational attainment.
Mean CMR parameters for each cohort are presented in Table 2. Before adjustment,
women who had used MHT 3 years had significantly smaller LV end-diastolic volume (117
±22 ml vs 124±22 ml; p<0.0001), LV end-systolic volume (46±12 ml vs 48±12 ml; p <0.005),
LV stroke volume (71±14 ml vs 75±14 ml; p<0.0001) and LA maximal volume (57±17 ml vs
61±17 ml; p<0.0001) compared to the cohort who had never used MHT. There was no
significant difference in LV mass between the two groups.
The effect of MHT use on LV and LA CMR parameters in fully adjusted models is detailed
in Table 3. Use of MHT for 3 years was associated with a significant reduction in LV
enddiastolic volume (123 ml vs 120 ml, effect size = -2.4%, 95% confidence interval [CI]: -4.2% to
-0.5%; p = 0.013), LV stroke volume (74 ml vs 72 ml, effect size = -3.1%, 95% CI: -5.1% to
-1.0%; p = 0.004) and LA maximal volume (60 ml vs 58 ml, effect size = -4.5%, 95% CI: -7.8%
to -1.0%; p = 0.012). These associations remained significant at a false discovery rate of 10%.
To further examine these associations produced by complete case analysis, multiple
Never used MHT
(n = 1091)
MHT use 3 years
(n = 513)
3 years on CMR parameters in fully-adjusted models.
Adjusted mean: never used MHT
Adjusted mean: MHT use > = 3 years
All parameters barring LV ejection fraction have been log-transformed and are therefore expressed as percentage change.
Model adjusted for age, age at menopause, ethnicity, height, weight, systolic blood pressure, diastolic blood pressure, smoking status, regular alcohol use, presence of
raised cholesterol, presence of diabetes, Townsend deprivation index and income.
imputation of missing values was performed and the analysis repeated. The same CMR
variables demonstrated significant associations with MHT use; these results are detailed in S1
Results of interaction analyses using age MHT as an interaction term in our regression
models are presented in Table 4 and Fig 2. Age significantly modified the association between
MHT use and CMR parameters with smaller chambers observed with advancing tertiles of
age: LV end-diastolic volume (47±60 years: β = 3.2%, 95% CI: -0.6% to 7.2%; 61±66 years: β =
-2.9%, 95% CI: -5.8% to 0.2%; 67±77 years: β = -6.2%, 95% CI: -9.0% to -3.3%; p for
interaction = 0.0005), LV end-systolic volume (47±60 years: β = 7.7%, 95% CI: 1.6% to 14.1%; 61±66
years: β = -3.1%, 95% CI: Ð7.6% to 1.6%; 67±77 years: β = -5.9%, 95% CI: -10.1% to -1.4%; p
for interaction = 0.001), LV stroke volume (47±60 years: β = 0.3%, 95% CI: -3.8% to 4.5%; 61±
66 years: β = -2.6%, 95% CI: -5.9% to 0.8%; 67±77 years: β = -6.4%, 95% CI: -9.4% to -3.2%; p
for interaction = 0.033), and LA maximal volume (47±60 years: β = 0.1%, 95% CI: -6.6% to
7.3%; 61±66 years: β = -1.2%, 95% CI: -6.6% to 4.6%; 67±77 years: β = -10.1%, 95% CI: -15.0%
to -5.0%; p for interaction = 0.006).
Results from sensitivity analyses examining the difference between CMR parameters in
MHT users 3 years and propensity-matched controls are presented in Table 5. There were
Effect sizes presented following adjustment for: duration of MHT use fitted as tertiles, age at menopause, ethnicity, height, weight, systolic blood pressure, diastolic
blood pressure, smoking status, regular alcohol use, presence of raised cholesterol, presence of diabetes, Townsend score and income.
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Fig 2. Interaction plots for age and MHT use. For every ten-year increment in age, there is a reduction in LV end-diastolic volume, LV end-systolic volume, LV stroke
volume and LA maximal volume. The relationship between age and CMR outcomes is of greater magnitude amongst MHT users than that amongst non-users.
429 matched participants in each group. As in multivariable regression models (Table 3), LV
end-diastolic volume (MHT users = 117.5 ml vs never users = 121.7 ml, mean difference =
-3.2%, 95% CI: -5.5% to -0.9%; p = 0.007), LV stroke volume (MHT users = 70.9 ml vs never
users = 73.8 ml, mean difference = -3.7%, 95% CI: -6.1% to -1.3%; p = 0.003) and LA maximal
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volume (MHT users = 56.8 ml vs never users = 59.4 ml, mean difference = -4.9%, 95% CI:
-8.9% to -0.8%; p = 0.019) were significantly lower in MHT users 3 years. S2 Table details the
balance between the co-variates both before and after propensity-matching.
In a population-based cohort of 1604 post-menopausal women free of known cardiovascular
disease, the present study identified the following: firstly, LV end-diastolic volumes and LA
maximal volumes were lower in women using MHT 3 years compared to those who had
never used MHT after accounting for potential confounders. Secondly, MHT use significantly
modified the relationship between advancing age and LV end-diastolic volume, LV
end-systolic volume and LA maximal volume. Thirdly, timing of commencement of MHT in relation
to the onset of menopause had no discernible impact of LV or LA volumes.
This study describes the relationship between MHT use and prognostically important
cardiac phenotypes and indicates lower LV end-diastolic and LA maximal volumes in women
who used MHT 3 years compared to those who never received treatment. Increases in LV
volumes±LV dilatation±is associated with cardiac decompensation and poor prognosis in a
range of cardiovascular diseases. Increases in end-diastolic volume and end-systolic volume
have been demonstrated to be associated with an increased risk of heart failure in
asymptomatic individuals [
] whilst reduction in LV volumes±indicative of reverse cardiac
remodelling±is associated with favourable outcomes [
]. Equivalently, LA enlargement, as
determined by LA maximal volume, is a robust and independent predictor of incident
cardiovascular events [
] whilst reduction in LA volumes (reverse remodelling) is associated
with lower mortality and risk of heart failure [
]. There was no significant difference in LV
mass between MHT users 3 years and those who had never used MHT. LV mass is one of
the most important cardiovascular imaging-derived phenotypes with increases in LV mass
predicting a higher incidence of cardiovascular events and mortality [
This study demonstrates that use of MHT significantly impacts upon age-related reduction
in LV and LA volumes. Recently published data detailing reference ranges for CMR imaging
derived from a strictly healthy UK Biobank cohort has demonstrated that LV end-diastolic
volume, end-systolic volume and LA maximal volume all decrease with advancing age [
keeping with findings from the never used MHT cohort. It is noteworthy, however, that use of
MHT results in a much more marked rate of diminishment in LV and LA volumes, even after
accounting for duration of MHT in addition to other confounders. Given that only 15% of
women were using MHT at the time of CMR examination, it appears that this is an effect that
persists, rather than being a contemporaneous result of being on treatment.
CMR is the most accurate and reproducible cardiac imaging modality and, when coupled
with a large cohort size, permits detection of subclinical changes in cardiac structure and
function. Whilst these subtle alterations may not result in any discernible impact to an individual
at a single point in time, if they persist it is possible that they will eventually lead to
prognostically relevant changes in cardiovascular outcomes. To our knowledge, this study is the first to
explore the relationship between MHT use and subclinical changes in cardiac structure and
function. Previous studies examining the impact of MHT on the cardiovascular system at the
subclinical stage have focused on atherosclerotic burden as detected by cardiac computed
tomography (CT). The most influential of these was a substudy of the Women's Health
Initiative which reported the coronary artery calcified-plaque burden was lower in women assigned
to MHT than in those assigned to placebo [
]. The more recent Early versus Late Intervention
Trial with Estradiol (ELITE) study , designed specifically to investigate the ªtiming hypothesisº in relation to atherosclerosis progression in post-menopausal women, did not show any
9 / 13
difference in plaque burden as assessed by cardiac CT in either early (<6 years) or late ( 10
years) menopause when compared to placebo although the authors did state that their sample
size may be insufficient to detect any difference.
Despite landmark randomised trials and systematic reviews [
] declaring that MHT does
not provide any protective effects from cardiac events or mortality, this has been challenged by
more recent studies examining both clinical end-points and surrogate markers of
atherosclerosis progression. What is clear is that there remains significant confusion regarding MHT's
benefit, or lack thereof, in relation to cardiovascular health. Discouragingly, it has been noted that
it is ªunlikelyº that additional large, prospective trials will be performed investigating MHT's
impact on cardiovascular disease due to existing controversy, fear of potential harm and the
expense associated with longitudinal follow-up [
]. We hope that our utilisation of
biomarkers provided by CMR in the context of a large-scale, population-based study such as UK
Biobank has provided a useful and novel method of examining MHT's influence on the
This study used a large population-based cohort, with uniform assessment of exposures,
covariates and outcomes. Importantly, there was no difference in socioeconomic status
between the two groups; previous studies have highlighted that women prescribed MHT are of
higher social class and educational attainment±and therefore, in general, healthier±than
women who do not receive MHT, thereby confounding results [
]. This is something that
we have attempted to control for in this data. However, there are several limitations that
should be considered in the interpretation of the findings. Firstly, the analysis was
cross-sectional, thus causality cannot be inferred from the associations demonstrated. Secondly, it was
not possible to explore longitudinal change in cardiac structure in relation to MHT use.
Thirdly, all menopause and MHT data was self-reported. Finally, we were not able to provide data on type of MHT due to significant amount of missing data.
In a large, population-based cohort of post-menopausal women free of cardiovascular disease,
use of MHT is not associated with adverse, subclinical changes in cardiac structure and
function. Indeed, we demonstrate significantly smaller LV and LA chamber volumes which have
been linked to favourable cardiovascular outcomes in other settings. Our findings provide a
novel way to examine the impact of MHT on the cardiovascular system; future work will focus
upon linkage of MHT use and CMR parameters to cardiovascular outcome data.
S1 Table. Effect of MHT use 3 years on CMR parameters in fully-adjusted models after
multiple imputation of missing values. Data was partially missing for 275/1604 (17%) of
participants. Between those with missing and no missing data, the groups were similar for all
covariates other than BMI (25.8 kg/m2 vs. 26.8 kg/m2, p = 0.003) and systolic blood pressure (133
mmHg vs. 137 mmHg, p = 0.009) which were higher in those with missing data. After multiple
imputation of missing values, the effect sizes are similar to those from complete case analysis
with the same CMR parameters realising significance. The complete case analysis detailed in
the main manuscript provides more conservative results.
S2 Table. Co-variate balance before and after propensity-matching. Propsensity matching
was performed using ªMatchItº package in R. Optimal matching technique was used.
10 / 13
This research has been conducted using the UK Biobank Resource under Application 2964.
The authors wish to thank all UK Biobank participants and staff.
Conceptualization: Mihir M. Sanghvi, Nicholas C. Harvey, Stefan K. Piechnik, Steffen E.
Data curation: Aaron M. Lee, Valentina Carapella.
Formal analysis: Mihir M. Sanghvi.
Funding acquisition: Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen.
Investigation: Mihir M. Sanghvi, Nay Aung, Jackie A. Cooper, JoseÂ Miguel Paiva, Filip Zem
rak, Kenneth Fung, Elena Lukaschuk, Valentina Carapella, Young Jin Kim, Steffen E.
Methodology: Mihir M. Sanghvi, Nay Aung, Jackie A. Cooper, Steffen E. Petersen.
Project administration: Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen.
Resources: Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen.
Software: Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen.
Supervision: Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen.
Validation: Mihir M. Sanghvi.
Visualization: Mihir M. Sanghvi.
Writing ± original draft: Mihir M. Sanghvi.
Writing ± review & editing: Mihir M. Sanghvi, Nay Aung, Jackie A. Cooper, JoseÂ Miguel
Paiva, Aaron M. Lee, Filip Zemrak, Kenneth Fung, Ross J. Thomson, Elena Lukaschuk,
Valentina Carapella, Young Jin Kim, Nicholas C. Harvey, Stefan K. Piechnik, Stefan Neubauer, Steffen E. Petersen.
11 / 13
follow-up (HERS II). JAMA. 2002; 288: 49±57. Available: http://www.ncbi.nlm.nih.gov/pubmed/
12090862 PMID: 12090862
7. American College of Obstetricians and Gynecologists. ACOG committee opinion. American College of
Obstetricians and Gynecologists;
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