The growing relevance of sex-specific risk factors

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Issue opens with an Editors’ Page entitled ‘The hypothesis: a new article type and platform for iconoclasts in medicine’ by Milton Packer from the Baylor University Medical Center in Dallas, TX, USA.1 In this contribution, Packer explains the rationale behind this new article category. These submissions, which propose novel or unconventional hypotheses that diverge from current thinking in the field, must be strongly supported by existing literature. The primary objective of these papers is to challenge conventional perspectives on the available evidence. This Issue continues with a focus on epidemiology, prevention, and healthcare policies. Pregnancy is a stress which may reveal or amplify sex-specific risk factors.2–9 The increasing use of assisted reproductive technology (ART) has raised concerns regarding its long-term cardiovascular safety due to potential hormonal imbalances and prothrombotic states. In a Fast Track article entitled ‘Cardiovascular safety of assisted reproductive technology: a meta-analysis’, Carlo Andrea Pivato from Humanitas University in Milan, Italy, and colleagues assess the long-term cardiovascular risk associated with fertility treatments in women.10 Following PRISMA guidelines, a systematic review and meta-analysis was conducted in MEDLINE (via PubMed) from inception to January 2024. Randomized, cohort, or case–control studies were included if fulfilling the following criteria: the association between ART and the subsequent cardiovascular outcome was reported and adjusted for confounding factors (at least age); the presence of a control group; and minimum 1 year follow-up. Effect size (ES) estimates of the association between fertility therapy and subsequent cardiovascular disease (CVD) were pooled using the DerSimonian and Laird random-effects model. Heterogeneity was assessed with the I2 index. Of the 7298 articles screened, 10 studies were included, encompassing >500 000 women undergoing ART and >36 000 000 controls. The analysis found no significant increase in the long-term risk of major adverse cardiovascular events (MACE), coronary heart disease, stroke, venous thromboembolism, hypertension, or diabetes. Assisted reproductive technology was associated with a lower risk of heart failure (ES 0.75, P = .01) (Figure 1). Systematic review and meta-analysis evaluating the association between assisted reproductive technology and cardiovascular risk in women. ART, assisted reproductive technology; CI, confidence interval; ES, effect size; MACE, major adverse cardiovascular events10 Pivato et al. conclude that ART use does not appear to be significantly associated with an increased long-term risk of CVD in women. The contribution is accompanied by an Editorial by Maria Christine Magnus from the Centre for Fertility and Health in Oslo, Norway.11 Magnus notes that existing studies looking at the risk of CVD among women who have used ART have a somewhat limited follow-up time. This means that while it has been possible to evaluate the short-term (10 years) risk of CVD, the more long-term risk remains to be clarified, particularly for outcomes which usually occur later in life, such as stroke and heart failure. So, while the research efforts looking into this topic have been considerable, they are limited by the datasets which have been available and the amount of follow-up time in those data sources. Further studies trying to fill in some of the noted knowledge gaps are therefore considered useful and necessary to hopefully finally establish whether or not women who undergo ART constitute a group at high risk of CVD. This research question remains open. In a Fast Track article entitled ‘Risk prediction of cardiovascular disease in the Asia-Pacific region: the SCORE2 Asia-Pacific model’, Steven Hageman from the University Medical Center Utrecht in the Netherlands, and colleagues sought to improve upon the estimation of 10 year CVD event risk for individuals without prior CVD or diabetes mellitus in the Asia-Pacific region by systematic recalibration of the SCORE2 risk algorithm.12 The sex-specific and competing risk-adjusted SCORE2 algorithms were systematically recalibrated to reflect CVD incidence observed in four Asia-Pacific risk regions, defined according to country-level World Health Organization age- and sex-standardized CVD mortality rates. Using the same approach as applied for the original SCORE2 models, recalibration to each risk region was completed using expected CVD incidence and risk factor distributions from each region. Risk region-specific CVD incidence was estimated using CVD mortality and incidence data on >8 000 000 individuals (>556 000 CVD events). For external validation, data from >9 500 000 individuals without previous CVD or diabetes were analysed in 13 prospective studies from 12 countries (>350 000 incident CVD events). The pooled C-index of the SCORE2 Asia-Pacific algorithms in the external validation datasets was 0.710. Cohort-specific C-indices ranged from 0.605 to 0.840. Estimated CVD risk varied several-fold across Asia-Pacific risk regions. For example, the estimated 10 year CVD risk for a 50-year-old non-smoker, with a systolic blood pressure of 140 mmHg, total cholesterol of 5.5 mmol/L, and HDL cholesterol of 1.3 mmol/L, ranged from 7% for men in low-risk countries to 14% for men in very-high-risk countries, and from 3% for women in low-risk countries to 13% for women in very-high-risk countries. The authors conclude that the SCORE2 Asia-Pacific algorithms have been calibrated to estimate 10 year risk of CVD for apparently healthy people in Asia and Oceania, thereby enhancing the identification of individuals at higher risk of developing CVD across the Asia-Pacific region. The contribution is accompanied by an Editorial by Mark Woodward from Imperial College London in the UK.13 Woodward highlights that where possible, for clinical, epidemiological, or emotive reasons, countries may prefer a score developed from their own data, or at least to have their own data included in the derivation set. For statistical reasons, to improve discrimination, inclusion of more risk factors, where available locally, would be preferred. The real value of this new score lies in the high-risk Asia-Pacific countries which are data poor. Chronic low-grade inflammation favours human atherosclerosis,14–19 while a Mediterrenian diet is protective.20 In a Clinical Research article entitled ‘Mediterranean diet, neutrophil count, and carotid intima-media thickness in secondary prevention: the CORDIOPREV study’, Hatim Boughanem from the Universidad de Cordoba in Spain, and colleagues explore the association between neutrophil count, and the intima-media thickness of common carotid arteries (IMT-CC), as well as the potential impact of long-term dietary interventions on these associations.21 A comprehensive analysis was conducted within the framework of the CORDIOPREV study, a long-term secondary prevention study involving dietary interventions with either a Mediterranean or a low-fat diet. The study evaluated the relationship between absolute neutrophil count and neutrophil-related ratios with IMT-CC at baseline and after 5 and 7 years of dietary intervention. At baseline, patients in the highest tertile of neutrophil count had a higher IMT-CC and number of carotid plaques, when compared with the lowest tertile (P < .01 and P < .05, respectively). Logistic regression analyses supported this association. Elevated neutrophil count, neutrophil-to-erythrocyte ratio, and neutrophil-to-HDL ratio were associated with an increased likelihood of having an IMT-CC >0.9 mm (odds ratio [OR] 1.17, 2.21, and 1.96, respectively), after adjustment for all variables, which was corroborated by linear regression. Interestingly, in patients exhibiting regression in IMT-CC after 7 years of follow-up, those following a Mediterranean diet showed a significant decrease in neutrophil count after 5 and 7 years (both with P < .05), compared with baseline. The authors conclude that these findings suggest that neutrophils may represent a promising target for preventing atherosclerosis. A Mediterranean diet could serve as an effective dietary strategy to reduce neutrophil levels and potentially slow the progression of atherosclerosis, offering a new neutrophil-reducing therapy concept. This manuscript is accompanied by an Editorial by Marta Guasch-Ferré from the University of Copenhagen in Denmark.22 Guasch-Ferré concludes that this study further confirms the significant cardiovascular benefits of the Mediterranean diet, highlighting its potential to reduce neutrophil counts and suggesting that these reductions could serve as a promising target for preventing atherosclerosis. Adverse pregnancy outcomes (APOs) are recognized as significant female-specific risk factors for CVD. A potential shared familial susceptibility between APOs and CVD has been proposed, but not thoroughly explored. In a Clinical Research article entitled ‘Adverse pregnancy outcomes, familial predisposition, and cardiovascular risk: a Swedish nationwide study’, Ängla Mantel from the Karolinska Institutet in Solna, Sweden, and colleagues employ a quasi-experimental family comparison design to investigate shared familial predisposition between APOs and CVD, by assessing risk of CVD in APO-exposed women and their APO-free sisters.23 In this nationwide population-based cohort study encompassing primiparous women, without prior CVD, with registered singleton births in the Swedish Medical Birth Register between 1992 and 2019, the authors grouped the participants into: women with ≥ 1 APO; APO-free sisters; and unrelated APO-free comparator women. All study participants were followed longitudinally, through linkage with national health registries from delivery until 2021, for the primary endpoint MACE, and its individual components: ischaemic heart disease (IHD), heart failure, and cerebrovascular events. Over a median follow-up of 14 years, APO-exposed women exhibited increased rates of CVD compared with APO-free comparators. APO-free sisters also exhibited elevated adjusted hazard ratios (aHRs) of MACE (aHR 1.39), heart failure (aHR 1.65), and cerebrovascular events (aHR 1.37) compared with the APO-free comparators, while no significant increase in IHD was observed. Within-family analysis revealed lower CVD rates in APO-free sisters compared with their APO-exposed counterparts, except for no significant difference in cerebrovascular events. The authors conclude that sisters of women with APOs face a moderately increased risk of CVD, suggesting a genetic and/or environmental influence on the association between APOs and CVD. These findings underscore the need to evaluate the effectiveness of targeted preventive measures in women with APOs and their sisters. The contribution is accompanied by an Editorial by Neha Pagidipati from the Duke University School of Medicine in Durham, NC, USA.24 Pagidipati notes that much work remains if we are to effectively prevent CVD in young women with APOs. Understanding that familial factors are important in predisposing women with APOs to CVD is a first step, but the next critical step is to understand exactly which factors—genetic, environmental, or both—are involved. If we can better elucidate what these factors are, then we can move towards prevention of CVD in women who develop APOs. One concrete contribution of this analysis is that we can now identify sisters of women who experience APOs as a group at elevated risk of future CVD, whether or not they develop APOs themselves. This could lead to more aggressive prevention efforts in this population that was previously unrecognized as being high risk. Ultimately, the authors should be congratulated for linking multiple national registries to provide unique insight into the relationship between familial factors, APOs, and future CVD. Clearly, when it comes to APOs and future CVD, family matters. In a Clinical Research article entitled ‘Coffee drinking timing and mortality in US adults’, Lu Qi and colleagues from the Tulane University School of Public Health and Tropical Medicine in New Orleans, USA identify the patterns of coffee drinking timing in the US population and evaluate their associations with all-cause and cause-specific mortality.25 This study included >40 500 adults from the NHANES 1999–2018 who had complete information on dietary data, and ∼1500 adults from the Women’s and Men’s Lifestyle Validation Study (WLVS and MLVS) who had complete data on a 7 day dietary record. Clustering analysis was used to identify patterns of coffee drinking timing. In this observational study, two distinct patterns of coffee drinking timing (morning-type [36% of participants] and all-day-type patterns [14% of participants]) were identified in NHANES and were validated in the WLVS and MLVS. During a median follow-up of 9.8 years, a total of 4295 all-cause deaths, 1268 CVD deaths, and 934 cancer deaths were recorded. After adjustment for caffeinated and decaffeinated coffee intake amounts, sleep hours, and other confounders, the morning-type pattern, was significantly associated with lower risks of all-cause (HR 0.84) and CVD-specific (HR 0.69) mortality as compared with non-coffee drinking. Coffee drinking timing significantly modified the association between coffee intake amounts and all-cause mortality (P-interaction = .031): higher coffee intake amounts were significantly associated with a lower risk of all-cause mortality in participants with morning-type pattern but not in those with all-day-type pattern (Figure 2). Coffee drinking timing, coffee intake amounts, and the risk of mortality. NHANES, National Health and Nutrition Examination Survey; CI, confidential interval; CVD, cardiovascular disease; HR, hazard ratio25 The authors conclude that coffee drinking in the morning may be more strongly associated with lower risk of mortality than coffee drinking later in the day. The manuscript is accompanied by an Editorial by Thomas Lüscher from the Royal Brompton and Harefield Hospitals GSTT in London, UK.26 Lüscher notes that the strength of the study is the large number of individuals included and the long follow-up of almost a decade. The prospective nature of the data collection, as regards coffee consumption and dietary habits, is a further strength. On the other hand, these cohort studies are not randomized trials and the data therefore provide only associations rather than causality. Indeed, it is possible that coffee drinkers differ from non-drinkers in many aspects. Overall, there is now substantial evidence that coffee drinking, particularly in the morning hours is likely to be healthy. Thus, Lüscher suggests drinking our coffee, but mainly in the morning! Please note that this suggestion comes from the President of the European Society of Cardiology. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Why couldn’t lipid-lowering therapies of ezetimibe combined with statin further reduce the risk of venous thromboembolism?’, Lingyan Lv from the The Affiliated Jiangyin Hospital of Xuzhou Medical University in China comment on the recent publication ‘Lipid lowering for prevention of venous thromboembolism: a network meta-analysis’ by Ioannis T. Farmakis from the University Medical Center of the Johannes Gutenberg University in Mainz, Germany, and colleagues.27,28 Huang et al. respond in a separate comment.29 The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, enarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.