European Heart Journal (2024) 45, 5105–5108 ISSUE @ A GLANCE

https://doi.org/10.1093/eurheartj/ehae837

Sex-specific risk factors: new light

shed on gestational diabetes
and obesity

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1,2
Filippo Crea
1
Center of Excellence of Cardiovascular Sciences, Ospedale Isola Tiberina – Gemelli Isola, Rome, Italy;
and 2Catholic University of the Sacred Heart, Rome, Italy

For the podcast associated with this article, please visit https://academic.oup. maternal obesity on offspring health.17 This review summarizes what
com/eurheartj/pages/Podcasts. is known about the offspring cardiovascular phenotype, describing a
mechanistic role for oxidative stress, metabolic inflexibility, and mito­
This Focus Issue on diabetes and metabolic disorders contains the chondrial dysfunction in mediating these impairments. It also discusses
‘Great debate: pre-diabetes is not an evidence-based treat­ the impact of secondary post-natal insults, which may reveal latent car­
ment target for cardiovascular risk reduction’ by Nikolaus diovascular deficits that originated in utero. Finally, current intervention­
Marx from the University Hospital Aachen in Germany, and collea­ al efforts and gaps of knowledge to limit the developmental origins of
gues.1 The authors note that with the increasing burden of diabetes cardiovascular dysfunction in offspring of obese pregnancy are
as a cause of macro- and microvascular disease linked to the epidemics highlighted.
of obesity, attention is being paid to dysglycaemic states that predict The increasing prevalence of diabetes, obesity, and their cardiometa­
and precede the development of type 2 diabetes.2–7 Such conditions, bolic sequelae present major global health challenges and highlight
termed pre-diabetes, are characterized by fasting plasma glucose, or shortfalls of current approaches to the prevention and treatment of
plasma glucose levels on an oral glucose tolerance test, or values of gly­ these conditions. In a State of the Art Review article entitled
cated haemoglobin intermediate between ‘normal’ values and those ‘Diabetes and obesity: leveraging heterogeneity for preci­
characterizing diabetes. These last are associated, in epidemiological sion medicine’, Paul Franks from Lund University in Sweden, and col­
terms, with a higher incidence of microvascular disease—mostly retin­ leagues indicate that representing the largest global burden of morbidity
opathy. There is little doubt that pre-diabetes has important prognostic and mortality, the pathobiological processes underlying cardiometa­
implications, especially for the occurrence of myocardial infarction, is­ bolic diseases are in principle preventable and, even when disease is
chaemic stroke, and peripheral arterial disease. It is disputed, however, manifest, sometimes reversable.18 Nevertheless, with current clinical
whether pre-diabetes is itself an actionable disease entity, in addition to and public health strategies, goals of widespread prevention and remis­
the risk factors characterizing it (Figure 1). Because of this uncertainty, sion remain largely aspirational. Application of precision medicine ap­
the latest European Society of Cardiology guidelines chose not to in­ proaches that reduce errors and improve accuracy in medical and
clude pre-diabetes as a treatment target for atherosclerotic cardiovas­ health recommendations has potential to accelerate progress towards
cular disease, at variance from the three previous editions of such these goals. Precision medicine must also maintain safety and ideally be
guidelines.8 This is spurring a debate, the Pro and Contra arguments cost-effective, as well as being compatible with an individual’s prefer­
featured in the present debate article. ences, capabilities, and needs. Initial progress in precision medicine
The consequences of cardiovascular and metabolic diseases during was made in the context of rare diseases, with much focus on pharma­
pregnancy are receiving growing interest.9–16 Pregnancy complicated cogenetic studies, owing to the cause of these diseases often being at­
by maternal obesity contributes to an increased cardiovascular risk in tributable to highly penetrant single gene mutations. By contrast, most
offspring, which is increasingly concerning as the rates of obesity and obesity and type 2 diabetes are heterogeneous in aetiology and clinical
cardiovascular disease are higher than ever before and still growing. presentation, underpinned by complex interactions between genetic
In a State of the Art Review article entitled ‘Pregnancy in obese and non-genetic factors. The heterogeneity of these conditions can
women and mechanisms of increased cardiovascular risk be leveraged for development of approaches for precision therapies.
in offspring’, Anna Cochrane from the University of Cambridge in Adequate characterization of the heterogeneity in cardiometabolic dis­
the UK, and colleagues note that there has been much research in hu­ ease necessitates diversity of and synthesis across data types and re­
mans and pre-clinical animal models to understand the impact of search methods, ideally culminating in precision trials and real-world

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5106 Issue @ a Glance

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Figure 1 A schematic representation of the time course of development of type 2 diabetes in the context of excess calorie intake. Impaired glucose
tolerance (IGT) and impaired fasting glucose (IFG) occur years before blood glucose exceeds the so-called diabetic threshold, above which microangio­
pathy starts to occur and type 2 diabetes is diagnosed. Much before the diagnosis of diabetes, however, the progressive decline in insulin sensitivity and
initially compensatory insulin hypersecretion lead to the earlier occurrence of macroangiopathy (large vessel atherosclerosis) and the development of
atherosclerotic vascular disease (circled in red). The time frame of IFG, higher than normal glycated haemoglobin (HbA1c), and—probably more rele­
vant—IGT revealed at the oral glucose tolerance test (OGTT) is termed ‘pre-diabetes’. Whether pre-diabetes is an actionable target for interventions,
independent of risk factors common to all vascular disease, is debated. CV, cardiovascular1

application of precision medicine approaches. This State of the Art Biobank. Linkage disequilibrium score regression analyses revealed
Review provides an overview of the current state of the science of pre­ that GD had a significant genetic correlation with coronary artery dis­
cision medicine, as well as outlining a roadmap for study designs that ease and myocardial infarction after Benjamini–Hochberg correction in
maximize opportunities and address challenges to clinical implementa­ ever-pregnant women. In Mendelian randomization analyses, odds ra­
tion of precision medicine approaches in obesity and diabetes. tios for coronary artery disease and myocardial infarction were 1.09
Observational studies have highlighted that gestational diabetes mel­ (1.01–1.17) and 1.12 per unit increase in the log-odds of genetic predis­
litus is associated with a higher risk of cardiovascular diseases, but the position to GD in ever-pregnant women, respectively. Further, type 2
causality remains unclear. In a Clinical Research article entitled diabetes and hypertension were identified as mediators for the causality
‘Gestational diabetes and future cardiovascular diseases: of genetic predisposition to GD on coronary artery disease.
associations by sex-specific genetic data’, Yeshen Zhang from Zhang et al. conclude that this study demonstrates a suggestive causal
the Southern Medical University in Guangzhou, China, and colleagues relationship between genetic predisposition to GD and the risk of cor­
investigated the causality between genetic predisposition to gestational onary artery disease, which is mainly mediated by type 2 diabetes and
diabetes (GD) and the risk of cardiovascular diseases using sex-specific hypertension. These findings highlight that targeting modifiable cardio­
Mendelian randomization analysis.19 Linkage disequilibrium score re­ metabolic risk factors may reduce the risk of coronary artery disease in
gression analysis and two-sample Mendelian randomization analysis women with a history of GD. This manuscript is accompanied by an
were applied to infer the genetic correlation and causality, respectively. Editorial by Maddalena Ardissino from the University of Cambridge
Mediation analysis was conducted using a two-step Mendelian random­ in the UK and Michael Honigberg from the Broad Institute of
ization approach. Sensitivity analyses were performed to differentiate Harvard and MIT in Cambridge, MA, USA.20 The authors note that
causality from pleiotropy. The genome-wide association study sum­ the study of Zhang et al. adds valuable insight to the ongoing investiga­
mary statistics for gestational diabetes mellitus were obtained from tion into the relationship between GD and cardiovascular disease.
the FinnGen consortium, while those for cardiovascular diseases Using Mendelian randomization, the results of the study contradict
were generated based on individual-level genetic data from the UK the notion of a direct causal link between GD and cardiovascular
Issue @ a Glance 5107

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Figure 2 Peripheral blood mononuclear cells (PBMCs) collected from women with gestational diabetes (GD), as well as cord blood mononuclear cells
(CBMCs) and human umbilical vein endothelial cells (HUVECs) from their newborns. Methyltransferase MLL1-induced activatory trimethylation of
histone H3 at lysine 4 (H3K4me3) in the promoter region of NF-κBp65 and NOX4 genes leads to their up-regulation and downstream inflammation
and oxidative stress. Enrichment of H3K4me3 in the NF-κBp65 promoter persists in PBMCs collected from adolescents born to GD women, and it is
associated with elevated plasma levels of inflammatory cytokines.21

disease, and rather support the notion of shared upstream risk factors (HUVECs) and cord blood mononuclear cells (CBMCs) were obtained
between GD and cardiovascular disease. Furthermore, when inter­ from umbilical cords. To investigate the role of MLL1, HUVECs were
preted from a clinical angle, the results suggest an important opportun­ exposed to the inhibitor MM102 or small interfering RNA (siRNA)
ity: even if GD itself is not causal, the excess cardiovascular disease transfection. PBMCs, CBMCs, and HUVECs showed an increase of
burden that has been demonstrated in affected women can be substan­ NF-κBp65, IL-6, ICAM-1, MCP-1, and VCAM-1 mRNAs in GD women
tially mitigated with high-quality primordial and primary prevention to as compared with controls. These findings were associated with
prevent and mitigate traditional cardiovascular risk factors. To effect­ H3K4me3 enrichment in the promoter of NF-κBp65. Higher
ively translate these insights into clinical practice, a coordinated multi­ H3K4me3 and cytokine levels were observed in GD adolescents as
disciplinary effort will be essential to leverage this unique primordial compared with control adolescents. MLL1 drove H3K4me3 not only
prevention opportunity in our efforts to reduce the global burden of on NF-κB p65, but also on the NOX4 promoter. Inhibition of MLL1
cardiovascular disease in women. blunted NF-κBp65 and NOX4 by modulating the inflammatory and oxi­
Hyperglycaemia during GD predisposes women and their offspring dative phenotype (Figure 2).
to later cardiometabolic disease. In a Translational Science article en­ The authors conclude that such a proof-of-concept study shows per­
titled ‘The inflammatory and oxidative phenotype of gesta­ sistence of MLL1-dependent H3K4me3 in offspring born to GD wo­
tional diabetes is epigenetically transmitted to the men, suggesting an epigenetic-driven transmission of maternal
offspring: role of methyltransferase MLL1-induced phenotype. These findings may pave the way for pharmacological re­
H3K4me3’, Nadia Di Pietrantonio from the Karolinska Institutet in programming of adverse histone modifications to mitigate abnormal
Stockholm, Sweden, and colleagues remind us that the hyperglycaemia- phenotypes underlying early atherosclerotic cardiovascular disease.
mediated epigenetic changes remain to be elucidated.21 The contribution is accompanied by an Editorial by Gian Paolo
Methyltransferase MLL1-induced trimethylation of histone 3 at lysine Fadini from the University of Padova in Italy.22 Fadini notes that the
4 (H3K4me3) activates an inflammatory and oxidative phenotype. public health implications of this research are significant and offer a
This epigenetic mark in GD women and its transmission to the offspring glimmer of hope. If the link between GD and cardio-metabolic diseases
were investigated. Peripheral blood mononuclear cells (PBMCs) were in offspring is not primarily genetic, then the risk passed down through
collected from GD and control women and also from adolescents generations is something we can potentially change. This realization
born to women of both groups. Human umbilical vein endothelial cells opens up exciting possibilities for investing in strategies that focus on
5108 Issue @ a Glance

epigenetic reprogramming of metabolism. While the idea of epigenetic 8. Marx N, Federici M, Schütt K, Müller-Wieland D, Ajjan RA, Antunes MJ, et al. 2023 ESC
drugs might seem like science fiction, it is worth remembering that our Guidelines for the management of cardiovascular disease in patients with diabetes. Eur
Heart J 2023;44:4043–140.
epigenetic footprint can also be reshaped with something as accessible
9. Crea F. Cardiovascular diseases in pregnancy, congenital heart disease, and arrhythmias:
as diet and lifestyle. These tried-and-true methods could be key players lessons from epidemiology. Eur Heart J 2023;44:699–702.
in turning the tide against the cardio-metabolic pandemic. It is a remind­ 10. Roos-Hesselink JW, van der Zande JA, Johnson MR. Pregnancy outcomes in women
er that in the complex world of epigenetics, we have the power to re­ with heart disease: how to improve? Eur Heart J 2023;44:1541–3.
write the story. 11. Justin Paul G, Anne Princy S, Anju S, Anita S, Cecily Mary M, Gnanavelu G, et al.
Pregnancy outcomes in women with heart disease: the Madras Medical College
The issue is also complemented by two Discussion Forum contribu­
Pregnancy And Cardiac (M-PAC) registry from India. Eur Heart J 2023;44:1530–40.
tions. In a commentary entitled ‘Subgroup effects of ticagrelor 12. Gulati M, Minhas A. Time to counter rising cardiovascular disease during pregnancy. Eur
treatment strategies: credibility considerations in an indi­ Heart J 2023;44:738–40.
vidual patient data meta-analysis’, Tengfei Li from the Gansu 13. Cauldwell M. Understanding the implications of hypertensive disorders in pregnancy in
University of Chinese Medicine in China and colleagues comment on women with heart disease. Eur Heart J 2022;43:3762–4.
14. van Steenbergen GJ, Tsang QHY, van der Heijden OWH, Vart P, Rodwell L,

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the recent publication ‘Ticagrelor monotherapy for acute cor­ Roos-Hesselink JW, et al. Timing of cardiac surgery during pregnancy: a patient-level
onary syndrome: an individual patient data meta-analysis of meta-analysis. Eur Heart J 2022;43:2801–11.
TICO and T-PASS trials’ by Yong-Joon Lee from the Yonsei 15. Crea F. A fresh look at non-traditional risk factors: pregnancy loss, anger, ultra-
University College of Medicine in Seoul, Korea.23,24 Lee et al. respond processed food, and low ambient temperature. Eur Heart J 2022;43:169–73.
16. Crea F. Challenges in the management of aortic stenosis, multiple valve disease, culture-
in a separate comment.25
negative endocarditis, and cardiac surgery during pregnancy. Eur Heart J 2022;43:
The editors hope that this issue of the European Heart Journal will be
2715–9.
of interest to its readers. 17. Cochrane ALK, Murphy MP, Ozanne SE, Giussani DA. Pregnancy in obese women and
Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, mechanisms of increased cardiovascular risk in offspring. Eur Heart J 2024;45:5127–45.
BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. 18. Franks PW, Sargent JL. Diabetes and obesity: leveraging heterogeneity for precision
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin medicine. Eur Heart J 2024;45:5146–55.
19. Zhang Y, Yu S, Chen Z, Liu H, Li H, Long X, et al. Gestational diabetes and future car­
Meyer for help with compilation of this article. diovascular diseases: associations by sex-specific genetic data. Eur Heart J 2024;45:
5156–67.
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