European Heart Journal (2024) 45, 5168–5170 EDITORIAL

https://doi.org/10.1093/eurheartj/ehae745 Epidemiology, prevention, and health care policies

Gestational diabetes and cardiovascular

disease: lessons for primordial prevention in
women and for interpreting Mendelian
randomization studies

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1,2,3,4 5,6,7,
Maddalena Ardissino and Michael C. Honigberg *
1
British Heart Foundation Cardiovascular Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; 2Victor Phillip Dahdaleh Heart and
Lung Research Institute, University of Cambridge, Cambridge, UK; 3National Heart and Lung Institute, Imperial College London, London, UK; 4Medical Research Council, London Institute of
Medical Sciences, Imperial College London, London, UK; 5Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA, USA; 6Cardiovascular Research
Center, Massachusetts General Hospital, Harvard Medical School, 185 Cambridge St. CPZN 3.187, Boston, MA 02114, USA; and 7Cardiology Division, Department of Medicine, Harvard
Medical School, Boston, MA, USA

Online publish-ahead-of-print 11 November 2024

This editorial refers to ‘Gestational diabetes and future cardiovascular diseases: associations by sex-specific genetic data’,
by Y. Zhang et al., https://doi.org/10.1093/eurheartj/ehae706.

Graphical Abstract

Gestational Marker of cardiovascular

diabetes disease risk
Shared risk factors between
gestational diabetes and
cardiovascular disease
Type 2 diabetes
Predisposition
to dysglycaemia Key targets for cardiovascular
Hypertension prevention after gestational
diabetes
Adiposity
Obesity

Coronary
artery disease

Gestational diabetes represents a risk signal for future cardiovascular disease and an opportunity for primordial and primary prevention.

Gestational diabetes (GD) is one of the most common complications of consequences of GD for foetal health (e.g. macrosomia, shoulder dys­
pregnancy, affecting up to 11% of women in Europe, and 31.5% of wo­ tocia, hypoglycaemia, and other neonatal morbidity) and maternal
men in Eastern European countries.1 In addition to immediate health (e.g. pre-eclampsia and gestational hypertension),2 previous

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
* Corresponding author. Tel: +1 617 726 1843, Email: [email protected]
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact [email protected] for
reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information
please contact [email protected].
Editorial 5169

studies have established that mothers with a history of GD are up to 1.01–1.17 per standard deviation of genetic risk for GD, P = .028).
seven times more likely to be diagnosed with type 2 diabetes (T2D) la­ However, they observe a remarkably consistent signal in men (OR
ter in life.3 Furthermore, multiple observational studies have demon­ 1.09; 95% CI 1.02–1.17 per standard deviation of genetic risk for GD,
strated that women with a history of GD are at higher risk of P = .015). In follow-up analyses examining GD as an outcome, the
cardiovascular disease later in life.4,5 However, the causal pathways authors identify highly significant MR associations of genetic predispos­
underlying the association of GD with cardiovascular disease are multi­ ition to blood glucose, T2D, body mass index, and obesity with the risk
factorial and complex. Observational studies to date have been limited of GD. In addition, they identify putative mediating effects of T2D and
by the potential influence of unmeasured confounding, including by fac­ hypertension in the association between GD and coronary artery dis­
tors that are notoriously difficult to measure and account for, such as ease, suggesting that these represent key targets for reducing cardiovas­
economic and socio-behavioural influences. In a study published in cular risk after GD.
the present issue of the European Heart Journal, Zhang and colleagues Though one might be tempted to speculatively read into the nominal
aimed to tackle this complex issue using genetic epidemiology.6 genetic association between GD and coronary artery disease, the re­

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Mendelian randomization (MR) is a genetic epidemiological method sults do not support a causal association for several reasons. The asso­
that leverages the randomness involved in the process of mating and al­ ciation was observed for both ever-pregnant females and males, which
lele assortment at conception, which effectively leads to randomization effectively demonstrates that this link cannot be taken to exclusively re­
of individuals to being at either high or low genetic risk for a given dis­ flect the influence of GD. When analysing a female-specific risk factor
ease or phenotype. Loosely parallel to randomization in a clinical trial, such as GD, observing the same association in males strongly suggests
this has the benefit of breaking the paths through which observational so-called ‘pleiotropy’—when a genetic instrument affects an outcome
confounding might influence, and therefore bias, association estimates. (here, coronary artery disease) through pathways other than the hy­
For this reason, this methodology can provide helpful corroboratory pothesized exposure (here, GD)—because men cannot develop GD.
evidence to support or refute a potentially causal effect of a risk factor In other words, the consistent finding observed in men supports con­
on an outcome.7,8 This finding can then be further scrutinized using founding by shared risk factors. This is further supported by additional
Bayesian co-localization analyses, which can be employed to investigate results presented in the paper, such as those demonstrating the influ­
whether, within the genomic regions under investigation, the same gen­ ence of genetic liability to hyperglycaemia and adiposity on GD risk,
etic variants cause the exposure and outcome.9 In addition, when a gen­ and phenome scanning identified considerable parallel effects of var­
etic association is established, MR can be used to provide helpful insight iants on other traditional cardiovascular risk factor phenotypes. For
regarding potential modifiable mediators of this relationship in a medi­ these reasons, the signal identified by the authors appears to relate
ation analysis framework.10 This is important for clinical translation, as it to shared cardiovascular risk factors such as elevated body mass index
can provide high-yield targets for selective monitoring and, potentially, and dysglycaemia rather than to GD itself (Graphical Abstract).
inform primordial and primary prevention approaches. However, even in the absence of strong evidence for a causal rela­
When thinking about the link between GD and cardiovascular dis­ tionship, these results reinforce the important message that GD repre­
ease, there are two key questions that inform clinical translation. The sents a ‘red flag’ or signal of long-term maternal cardiovascular risk and
first question is whether the average patient with GD has a higher may warrant a targeted approach for cardiovascular disease prevention.
risk of developing cardiovascular disease than the average patient with­ The literature consistently demonstrates that women affected by GD
out GD. In other words, is GD a marker of greater cardiovascular risk in and other adverse pregnancy outcomes experience accelerated cardio­
later life? Based on extensive observational evidence published to vascular disease,12 underscoring that the current guideline-directed ap­
date,11 we know this to be the case. The second question is whether proaches for prevention in the general population are insufficient for
this higher risk is causally related to GD itself, or whether it is related these high-risk subgroups. Having established the importance of heigh­
to the constellation of upstream risk factors for GD (e.g. obesity and tened awareness for traditional cardiovascular risk factor surveillance in
T2D) that are also cardiovascular disease risk factors (i.e. confounding women with GD, a key issue is the optimal implementation of post-
by shared risk factors). This latter question represents the focus of the partum screening programmes to prevent, detect, and treat cardiovas­
study of Zhang et al. Ultimately, their results do not support the notion cular risk factors. Despite the large body of evidence supporting obstet­
that it is GD itself that causes later life cardiovascular disease, but rather ric morbidity as a marker for worse long-term cardiovascular health,
that it probably relates to overlapping traditional cardiovascular risk evidence is still lacking on when, and how, we should screen affected
factors. patients.13–15 Furthermore, setting up these programmes requires a
In the main analyses of the study, Zhang et al. leverage genome-wide proactive allocation of health system resources, starting with clearly es­
association data from FinnGen to extract genetic instruments for GD as tablishing the remit of responsibilities of different specialties: should
the exposure of interest and the UK Biobank as the outcome dataset these screening programmes fall under primary care, obstetrics, cardi­
for multiple cardiovascular diseases, including coronary artery disease, ology, or endocrinology services? The correct answer may vary across
myocardial infarction, heart failure, atrial fibrillation, cerebrovascular and within countries, and we need to build and rigorously test new
diseases, aortic aneurysm, peripheral vascular disease, and pulmonary health models to tackle this issue.
embolism. Using these datasets, the authors employ the MR statistical In conclusion, the study of Zhang et al. adds valuable insight to the
framework to test the genetic association between GD and cardiovas­ ongoing investigation into the relationship between GD and cardiovas­
cular disease separately in ever-pregnant women, never-pregnant wo­ cular disease. Using MR, the results of the study contradict the notion of
men, and men, with these latter two groups functioning as ‘negative a direct causal link between GD and cardiovascular disease, and rather
controls’. Although the authors do not find a statistically significant gen­ support the notion of shared upstream risk factors between GD and
etic association between GD in ever-pregnant women and multiple car­ cardiovascular disease. These findings represent an important lesson
diovascular disease outcomes after correction for multiple testing, they for the conduct and interpretation of MR experiments in highlighting
do identify a nominally significant association between GD and coron­ the value of incorporating negative controls. Furthermore, when inter­
ary artery disease (odds ratio [OR] 1.09; 95% confidence interval [CI] preted from a clinical angle, the results suggest an important
5170 Editorial

opportunity: even if GD itself is not causal, the excess cardiovascular 5. Gunderson EP, Sun B, Catov JM, Carnethon M, Lewis CE, Allen NB, et al. Gestational
diabetes history and glucose tolerance after pregnancy associated with coronary artery
disease burden that has been demonstrated in affected women can
calcium in women during midlife. Circulation 2021;143:974–87. https://doi.org/10.1161/
be substantially mitigated with high-quality primordial and primary pre­ CIRCULATIONAHA.120.047320
vention to prevent and mitigate traditional cardiovascular risk factors. 6. Zhang Y, Yu S, Chen Z, Liu H, Li H, Long X, et al. Gestational diabetes and future car­
To effectively translate these insights into clinical practice, a coordi­ diovascular diseases: associations by sex-specific genetic data. Eur Heart J 2024;45:
nated multidisciplinary effort will be essential to leverage this unique 5156–67. https://doi.org/10.1093/eurheartj/ehae706
7. Bennett DA, Holmes MV. Mendelian randomisation in cardiovascular research: an intro­
primordial prevention opportunity in our efforts to reduce the global duction for clinicians. Heart 2017;103:1400–7. https://doi.org/10.1136/heartjnl-2016-
burden of cardiovascular disease in women. 310605
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Guidelines for performing Mendelian randomization investigations. Wellcome Open

Declarations Res 2020;4:186. https://doi.org/10.12688/wellcomeopenres.15555.2

9. Giambartolomei C, Vukcevic D, Schadt EE, Franke L, Hingorani AD, Wallace C, et al.
Bayesian test for colocalisation between pairs of genetic association studies using sum­
Disclosure of Interest

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mary statistics. PLoS Genet 2014;10:e1004383. https://doi.org/10.1371/journal.pgen.
M.C.H. reports consulting fees from Comanche Biopharma, advisory 1004383
10. Carter AR, Sanderson E, Hammerton G, Richmond RC, Davey Smith G, Heron J, et al.
board service for Miga Health, site principal investigator work for Mendelian randomisation for mediation analysis: current methods and challenges for
Novartis, and research support from Genentech. M.A. declares no dis­ implementation. Eur J Epidemiol 2021;36:465–78. https://doi.org/10.1007/s10654-021-
closure of interest for this contribution. 00757-1
11. Crump C, Sundquist J, McLaughlin MA, Dolan SM, Govindarajulu U, Sieh W, et al.
Adverse pregnancy outcomes and long term risk of ischemic heart disease in mothers:
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Correction https://doi.org/10.1093/eurheartj/ehae701
Online publish-ahead-of-print 4 October 2024
.....................................................................................................................................................................................

Correction
This is a correction to:
• Claudia Stöllberger, Josef Finsterer, Birke Schneider, Haemodynamic changes after interventional closure of the left atrial appendage may
facilitate peri-device leaks, European Heart Journal, Volume 45, Issue 41, 1 November 2024, Pages 4443–4444, https://doi.org/10.1093/
eurheartj/ehae458
• Athanasios Samaras, Apostolos Tzikas, Left atrial appendage occlusion leaks matter: the cryptic interplay of post-procedural haemodynamic
changes and device surveillance, European Heart Journal, Volume 45, Issue 41, 1 November 2024, Pages 4445–4446, https://doi.org/10.1093/
eurheartj/ehae459
In the originally published version of the below-listed manuscripts the first paragraph incorrectly stated that the commentary was referring to
“‘Inorganic nitrate benefits contrast-induced nephropathy after coronary angiography for acute coronary syndromes: the NITRATE-CIN
trial’, by D.A. Jones et al., https://doi.org/10.1093/eurheartj/ehae100”.
This was incorrect and the papers actually refer to “’Residual leaks following percutaneous left atrial appendage occlusion and outcomes: a
meta-analysis’, by A. Samaras et al,. https://doi.org/10.1093/eurheartj/ehad828”
This error has been corrected.
© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact repri­
[email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site
—for further information please contact [email protected].