Forgotten cardiovascular risk factors: pregnancy complications and preterm birth, bullying, periodontal disease, and hypoxic burden

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. The assessment of cardiovascular risk has been pioneered by the Framingham Study when its investigators showed that age, blood pressure, smoking, cholesterol, and diabetes were major predictors of myocardial infarction, stroke, and death.1 It was, however, obvious from the start that, although these factors were very useful, they were not really precise. Thus, there must be many other risk factors that determine cardiovascular outcome, such as inflammation,2 environemental hazards,3 and genetics4–6 and epigenetics.7–9 Some of these forgotten risk factors are discussed in this issue. It starts with a Review entitled ‘Mechanisms linking preterm birth to onset of cardiovascular disease later in adulthood’ by Jawahar L. Mehta and colleagues from the University of Arkansas in Little Rock, Arkansas, USA.10 The authors remind us that cardiovascular disease rates in adulthood are high in premature infants and discuss potential pathways such as dyslipidaemia, oxidant stress, inflammation, epigenomic changes, and gut microbiota. Interestingly, probiotic bacteria such as the mucin-degrading bacterium Akkermansia muciniphila reduce inflammation and prevent heart disease in animal models which, among other interventions, may provide a novel potential pathway to curtail the adverse effects of prematurity on the cardiovascular system (Figure 1). Interplay and crosstalk between elevated oxidative stress, an immature immune response, and altered reninangiotensinaldosterone system responses that can prime a preterm infant for development of cardiovascular disease later in life. Oxidative stress results in formation of ox-LDL which is taken up by macrophages which develop into foam cells. These cells release large amounts of reactive oxygen species and growth factors such as angiotensin II; the latter stimulates Type 1 receptor AT1R on endothelial cells and smooth muscle cells. Reactive oxygen species and AT1R activation repress endothelial nitric oxides synthase activity, resulting in reduced constitutive NO production and vasoconstriction. The immature immune response results in an imbalance of pro-inflammatory and anti-inflammatory cytokines, with enhancing effects on oxidative stress and vasoconstriction. Inflammatory cells under the influence of pro-inflammatory cytokines activate iNOS resulting in formation of large amounts of NO which can have a tissue injurious effect. Direct and possible long-term effects are listed at the bottom of the figure (from Bavineni M, Wassenaar TM, Agnihotri K, Ussery DW, Lüscher TF, Mehta JL. Mechanisms linking preterm birth to onset of cardiovascular disease later in adulthood. See pages 1107–1112). Pregnancy can be associated with multiple cardiovascular complications such as pre-eclampsia,11 cardiomyopathy,12 and coronary artery dissection,13,14 among others. This issue is further pursued in the article entitled ‘Does pregnancy complication history improve cardiovascular disease risk prediction? Findings from the HUNT study in Norway’ wherein Amanda Markovitz and colleagues from the Harvard School of Public Health in Boston, Massachusetts, USA evaluated whether history of pregnancy complications such as pre-eclampsia, gestational hypertension, preterm delivery, or small for gestational age improves risk prediction for cardiovascular disease.15 This population-based, prospective cohort study linked data from the HUNT Study, Medical Birth Registry of Norway, validated hospital records, and the Norwegian Cause of Death Registry. Using the NORRISK 2 risk prediction model, the authors calculated 10-year risk of non-fatal myocardial infarction, fatal coronary heart disease, and non-fatal or fatal stroke based on established risk factors and evaluated whether adding pregnancy complications would improve the model fit and reclassification. Among 18 231 women who were parous, ≥40 years of age, and cardiovascular disease-free at baseline, 39% had any pregnancy complication and 5% experienced a cardiovascular event during 8 years. While pre-eclampsia and a small for gestational age baby were associated with cardiovascular disease in unadjusted models, with hazard ratios of 1.96 and 1.46, respectively, only pre-eclampsia remained predictive after adjusting for established risk factors, with a hazard ratio of 1.60. Thus, pre-eclampsia independently predicted cardiovascular disease after adjustment for confounders; however, adding pre-eclampsia, gestational hypertension, preterm delivery, and small for gestational age only marginally improved prediction. These findings are further discussed in an Editorial by Denise Hilfiker-Kleiner from the Hannover Medical School in Germany.16 Psychological stress has long been implicated in cardiovascular disease,17–19 but well-being at work is a novel aspec. In their article ‘Workplace bullying and workplace violence as risk factors for cardiovascular disease: a multi-cohort study’ Tianwei Xu and colleagues from the Kobenhavns Universitet in Denmark20 assessed this in 79 201 working men and women, aged 18–65 years and free of cardiovascular disease. Nine percent of these reported being bullied at work and 12% had been exposed to workplace violence. After adjustment for age, sex, country of birth, marital status, and educational level, being bullied at work was associated with cardiovascular disease with a hazard ratio of 1.59 and workplace violence with a hazard ratio of 1.25. The population-attributable risk was 5.0% for workplace bullying and 2.9% for workplace violence. The excess risk remained similar in analyses with different follow-up lengths, cardiovascular risk stratifications, and after additional adjustments. Importantly, dose–response relationships were observed for both workplace bullying and violence. Thus, bullying and violence are common at workplaces and are a risk for later cardiovascular disease. The intriguing findings are put into context in an Editorial by Christoph Herrmann-Lingen from the University of Göttingen Medical Centre in Germany.21 Numerous bacteria inhabit our body and affect the cardiovascular system as well as clinical outcome.22–24 In the oral cavity, they are involved in periodontal disease, dental caries, and tooth loss, all events that have been implicated in cardiovascular disease. In their article entitled ‘Improved oral hygiene care attenuates the cardiovascular risk of oral health disease: a population-based study from Korea’, Si-Hyuck Kang and colleagues from the Seoul National University Bundang Hospital in the Republic of Korea evaluated whether oral hygiene behaviour can alleviate cardiovascular risk using a nationwide population-based cohort of 247 696 healthy adults aged 40 years or older.25 After a median follow-up of 9.5 years, 14 893 major cardiovascular events occurred, including cardiac death, myocardial infarction, stroke, and heart failure. Cardiovascular risk was increased by periodontal disease, dental caries, or tooth loss (Figure 2). On the other hand, after multivariable adjustment, tooth brushing once or more a day was associated with a 9% lower risk of cardiovascular events. Regular dental visits (at least once a year) for professional cleaning also reduced cardiovascular risk by 14%. Thus, improved oral hygiene may modify the association between oral health and cardiovascular diseases. These practically relevant findings are further discussed in an informative Editorial by Stefano Masi from the University College London in the UK.26 (from Xu T, Magnusson Hanson LL, Lange T, Starkopf L, Westerlund H, Madsen IEH, Rugulies R, Pentti J, Stenholm S, Vahtera J, Hansen ÅM, Virtanen M, Kivimäki M, Rod NH. Workplace bullying and workplace violence as risk factors for cardiovascular disease: a multi-cohort study. See pages 1124–1134). Sleep apnoea is a well-established risk factor for stroke, infarction, and death.27,28 The apnoea–hypopnoea index, or AHI, is commonly used to determine the severity of sleep apnoea.29 However, it poorly predicts the adverse outcomes in such patients, most probably because the AHI is a frequency measure that does not adequately capture disease burden. In their article ‘The hypoxic burden of sleep apnoea predicts cardiovascular disease-related mortality: the Osteoporotic Fractures in Men Study and the Sleep Heart Health Study’ Ali Azarbarzin and colleagues from the Harvard Medical School in Boston, Massachusetts, USA evaluated the ‘hypoxic burden’ in 2743 men of the Outcomes of Sleep Disorders in Older Men study and 5111 middle-aged and older adults of the Sleep Heart Health Study.30 Unlike the AHI, hypoxic burden strongly predicted cardiovascular, but not all-cause mortality. Individuals of the Outcomes of Sleep Disorders in Older Men study with hypoxic burden in the top two quintiles had hazard ratios of 1.60 and 2.04, respectively. Similarly, those of the Sleep Heart Health Study with hypoxic burden in the highest quintile had a hazard ratio of 1.96. Thus, ‘hypoxic burden’, an easily derived signal from an overnight sleep study, predicts cardiovascular mortality. The findings suggest that not only the frequency, but also the depth and duration of sleep-related upper airway obstructions, are prognostically important. The issue is complemented with a Current Opinion entitled ‘UK Biobank: opportunities for cardiovascular research’ by Thomas Littlejohns and colleagues from the University of Oxford in the UK.31 The authors note that previous cohorts have been limited by small sample sizes and/or a lack of diverse outcomes, thereby restricting the potential research questions that can be explored. To address this, UK Biobank was established as a population-based prospective study with data and samples of unparalleled breadth and depth from 500 000 UK adults, recruited between 2006 and 2010. Incident health outcomes are captured through linkage to electronic medical records over the long term. The biological samples collected have enabled biochemical measurements and genome-wide genotyping to be performed for the full cohort. Enhanced measures are being performed on large subsets, including the largest multimodal imaging study involving 100 000 participants, physical activity monitoring of 100 000 participants, and a series of web-based questionnaires from >100 000 participants. As a result, UK Biobank offers an invaluable opportunity to conduct novel epidemiological research focused on cardiovascular disease and its associated environmental and genetic risk factors, as well as how these factors interact with non-cardiovascular outcomes. As an open-access resource, UK Biobank provides researchers from around the world with an opportunity to generate findings that will positively impact the prevention, treatment, and diagnosis of cardiovascular disease in the foreseeable future. The editors hope that this issue of the European Heart Journal will be of interest to its readers. With thanks to Amelia Meier-Batschelet for help with compilation of this article.