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Corresponding author. Laboratory of Experimental Cardiology, University Medical Center Utrecht, Room number G03.644, P.O. Box 85500, 3508 GA Utrecht, The Netherlands.
Affiliations
Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The NetherlandsDepartment of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The NetherlandsICIN-Netherlands Heart Institute, Utrecht, The NetherlandsDepartment of Cardiology, University Medical Centre Utrecht, The NetherlandsDurrer Center for Cardiogenetic Research, ICIN-Netherlands Heart Institute, Utrecht, The NetherlandsInstitute of Cardiovascular Science, Faculty of Population Health Sciences, University College London, London, United Kingdom
Laboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The NetherlandsDepartment of Clinical Chemistry and Haematology, University Medical Center Utrecht, Utrecht, The Netherlands
]. This phenomenon has led to the under appreciation of sex-differences in cardiovascular disease (CVD) from an etiological, prognostic, diagnostic and therapeutic perspective. Several initiatives to promote women's health, such as the Women's Health Initiative [
] have been initiated and have changed the practice of cardiovascular disease prevention in women over the past decade. This ultimately led to the first guidelines for cardiovascular disease prevention in women by the American Heart Association in 1999 [
]. These initiatives have increased the awareness that medical practice in cardiovascular disease may differ between men and women and that the ‘one size fits all’ approach may not hold. This special issue of the journal is dedicated to sex-differences in CVD risk factors, presentation, underlying mechanisms, treatment and cross-links with other diseases such as autoimmune diseases.
One of the factors that may worsen outcome in women as compared to men is the perception of cardiovascular risk and the decision to seek medical care when experiencing complaints [
]. Research shows that more than half of the women would still be hesitant to call the emergency number when thinking they are experiencing a myocardial infarction. Several studies report that time from symptoms to first medical contact as well as time from hospital arrival to reperfusion is significantly longer in women as compared to men [
]. The reported median delays are between 15 min to more than an hour in women. This fact underscores the need for campaigns educating women and the primary care system about the importance of recognizing a-specific symptoms in order to improve survival.
Indeed, in the last decade intensive public efforts to educate women about their risk of heart disease have been quite successful as a recent survey showed that awareness of heart disease among women nearly doubled in 10 years [
]. Given the positive correlation between awareness and cardiovascular disease risk reductions in women, it is important that the emphasis on these campaigns remains high.
Among sex differences in clinical presentation of CVD, more women than men present with acute coronary syndromes but non-obstructed arteries [
]. The review of F. Crea and coworkers in this issue of Atherosclerosis summarizes the clinical presentation of CVD in men and women, and underscores the sex-differences in underlying pathology. Cardiac ischemia due to coronary microvascular obstruction is more prevalent in women as compared to men, gives rise to chest pain in women, and is subject to underdiagnosis. In addition, increasing evidence points towards coronary microvascular endothelial inflammation as cause for heart failure with preserved ejection fraction (HFpEF) [
Novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.
], a condition that affects women more than men. Similarly to coronary microvascular obstruction, HFpEF is also subject to under-diagnosis due to the lack of biomarkers that are implicated in the disease process. The Dutch Queen of Hearts consortium aims to discover and validate new biomarkers related to microvascular endothelial inflammation to improve the diagnosis of HFpEF [
Next to differences in the microvasculature, also differences in the pathological substrate of macrovascular obstruction are quite prominent between men and women. This is reviewed by Yahagi [
] and coworkers who summarize pathological observations that are considered as the underlying substrate for CVD. Women have more stable plaques, and more plaque erosion as underlying cause for sudden cardiac death as compared to men in whom more vulnerable plaques and more plaque rupture are reported under similar conditions [
]. This is supported by research from our group showing that women undergoing carotid endarterectomy have more stable plaques as compared to men. Moreover, the predictive value of plaque haemorrhage as predictor for secondary outcome was conveyed to men [
Sex is associated with the presence of Atherosclerotic plaque hemorrhage and modifies the relation between plaque Hemorrhage and cardiovascular outcome.
], the role of smoking and the menopause is being discussed as factors that could be causally related with accelerated CVD in women. It has been suggested that sex hormone status explains the differences between men and women and their progression to CVD. Indeed, estrogens in women appear to protect against CVD as loss of estrogens during and after menopause goes hand in hand with an increased cardiovascular risk. However, whether hormone replacement therapy after menopause confers cardiovascular benefit or harm remains controversial and appears to depend on time since menopause at the initiation of hormone replacement therapy.
Women have specific risk factors for CVD that are related to pregnancy disorders such as gestational diabetes, hypertension and preeclampsia as well as endocrine changes in women of reproductive age such as early menopause. These risk factors are reviewed by Appelman [
] and coworkers who also compare risk factors for CVD between men and women. The risk factor that appears to be most sex-specific for CVD is prolonged smoking which appears to be more harmful for women than for men.
Fig. 1Schematic overview of sex differences in cardiovascular disease. Although risk factors for CVD overlap between sexes, some sex-specific risk factors have been identified such as pregnancy disorders, awareness of being at risk for CVD and the regulatory role of sex chromosomes.
] and coworkers who discuss the role of genetics and sex chromosomes in particular. Sex chromosomes are beginning to be recognized as important players in sex differences in disease development, independent of sex hormones [
]. The human X and Y chromosomes evolved from a pair of autosomes over the past 160 million years. The sex chromosomes differentially evolved into a relatively large, gene-rich X chromosome and a small, gene-poor Y chromosome. Only 3% of ancestral genes survived on the human Y chromosome compared to 98% on the X chromosome. It was recently discovered that the genes conserved on Y that are expressed in cells and tissue types throughout the body are involved in decoding and interpreting the entirety of the genome [
]. The Y chromosome is present exclusively in men and contains the sex-determining region, the primary determinant of testicular development, spermatogenesis and masculinization. The Y chromosome has mostly been excluded from the larger genome-wide association studies (GWAS), due to technical difficulties and also due to the thought that the Y chromosome could be considered as genetic wasteland [
], This under-representation of X in GWAS is particularly striking in the context of significant (≈5%) contribution of X chromosome to the overall content of the human protein-coding genome. Regulation of the X chromosome is especially of interest in diseases that have a different prevalence between sexes. Inactivation of the X chromosome in women entails the random silencing of one of the two X chromosomes to compensate for the fact that men have only one, so called dosage compensation. The mechanism of X chromosome inactivation is however incomplete and flexible so it regulates gene expression between sexes, individuals and tissues [
]. The X chromosomes contain information involved in inflammation, and contribute largely to autoimmune diseases that are highly female-specific. Biological targets for X-linked miRNAs are amongst others FOXP3, CTLA-4, PDCD1 and members of the CBL and SOCS ubiquitin family, all related to inflammation and endothelial function [
]. Indeed it has been suggested that X-chromosome-genomic context affects X-located miRNAs thereby contributing to the enhanced immune response in women [
]. X chromosome instability (loss of the second X) in peripheral blood cells is directly linked to the development of female specific autoimmune diseases and cardiovascular diseases [
Autoimmune diseases have a high prevalence in women and also associate with cardiovascular disease risk. In autoimmune diseases the immune response to self-antigens results in damage or dysfunction of tissues. They can occur systemic or can affect specific organs or body systems. For most autoimmune diseases there is a clear sex difference in prevalence. In autoimmune disorders such as Addison's disease, scleroderma, systemic lupus erythematosus (SLE), Sjorgen's syndrome, and thyroiditis, females represent >85% of cases whereas myocarditis appears to be male-specific [
]. The microvasculature in women may play an important role in the predisposition of women with autoimmune diseases to develop accelerated CVD as reviewed by Gianturco and coworkers in this issue [
Gianturco L, Bodini BD, Atzeni F et al. Cardiovascular and autoimmune diseases in females: the role of microvasculature and dysfunctional endothelium. Atherosclerosis (in press).
In summary, there are profound sex-differences in heart disease. This issue of Atherosclerosis is dedicated to this timely topic which is increasingly being acknowledged. Further research initiatives with the objective to personalize cardiovascular care for men and women are eagerly awaited.
Funding
The authors are supported by the Dutch Heart Foundation (2013T084). More information on this Queen of Hearts program can be found at www.queen-of-hearts.eu.
References
Melloni C.
Berger J.S.
Wang T.Y.
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Representation of women in randomized clinical trials of cardiovascular disease prevention.
Novel paradigm for heart failure with preserved ejection fraction: comorbidities drive myocardial dysfunction and remodeling through coronary microvascular endothelial inflammation.
Sex is associated with the presence of Atherosclerotic plaque hemorrhage and modifies the relation between plaque Hemorrhage and cardiovascular outcome.
Gianturco L, Bodini BD, Atzeni F et al. Cardiovascular and autoimmune diseases in females: the role of microvasculature and dysfunctional endothelium. Atherosclerosis (in press).
Serum uric acid (SUA) elevation has been largely addressed in the past as a possible risk factor for cardiovascular disease. However, uric acid has not clearly emerged as independent risk factor for coronary artery disease. Several studies in literature have assessed sex-related differences in the association between elevated SUA levels and cardiovascular events with conflicting results. Therefore, aim of the current study was to evaluate the relationship between uric acid levels and the extent of coronary artery disease in male and female patients undergoing coronary angiography.
The presence of proinflammatory monocytes/macrophages (CD14+CD16+) has been documented in conditions of inflammation, such as atherosclerosis. We analysed the proportion of proinflammatory monocytes/macrophages in perirenal and perivascular fat in healthy living kidney donors with regard to sex and age reflecting reproductive status in women; therefore, women were further divided to younger and older group (younger and older than 51 years) reflecting potential age of menopause. Monocyte/macrophages were identified as CD14+ mononuclear cells and divided into subpopulations based on the co-expression of CD16.
Parental stroke is a risk factor for stroke among the offspring. Carotid artery intima-media thickness (IMT) is a widely regarded surrogate marker for atherosclerosis and a predictive marker for stroke. This study examines whether parental stroke is associated with IMT progression.
Recent studies have demonstrated an association between serum uric acid (SUA) levels and metabolic syndrome (MetS). However, paucity of available data regarding the cause and effect relationship between SUA and MetS in healthy adults is still a big challenge which remains to be studied. Therefore, we investigated whether SUA predicts new onset of MetS in a population-based cohort study.
Cardiovascular (CV) diseases are becoming increasingly frequent and associated with a high incidence of CV events, disability and death. It is known that there is a relationship between CV burden and systemic autoimmune diseases (SADs) that is mainly due to inflammation and autoimmunity, but the other mechanisms underlying the high CV risk of SAD patients have not yet been fully clarified. The aim of this review article is to discuss some of the specific factors associated with the accelerated atherosclerosis (ATS) characterising SADs (female sex, the microcirculation and the endothelium) in order to highlight the importance of an early diagnosis and the prompt implementation of preventive measures, as well as the possible role of new therapeutic strategies such as vaccine immunomodulation.
Cardiovascular disease is the leading cause of mortality in chronic kidney disease (CKD). Serum phosphate has been associated to cardiovascular disease in the general population and this effect seems to be different according to sex. In the present study we analyze the effect of phosphate on subclinical atherosclerosis in the NEFRONA population and its effect depending on sex.
Vascular calcification has been associated inconsistently to low bone mineral density and fractures. The aims of the present study were to investigate the associations between coronary artery calcification (CAC) and BMD change, BMD and fracture risk in elderly subjects of the population-based Rotterdam Study.
Coronary artery disease (CAD) affects both men and women. Cardiovascular biomarkers have been suggested to relate to CAD severity, but data on sex-specificity is scarce. Therefore, we investigated the association of established biomarkers with the severity of CAD in stable patients undergoing coronary angiography in a sex-specific manner.
Age at first atherosclerotic event is typically older for women vs. men; monthly iron loss has been postulated to contribute to this advantage. We investigated the relationship between an MRI-based arterial wall biomarker and the serum inflammatory biomarker high-sensitivity C-reactive protein (hsCRP) in perimenopausal women vs. men.
Sex differences in incidence and prevalence of and morbidity and mortality from cardiovascular disease are well documented. However, many studies examining the genetic basis for cardiovascular disease fail to consider sex as a variable in the study design, in part, because there is an inherent difficulty in studying the contribution of the sex chromosomes in women due to X chromosome inactivation. This paper will provide general background on the X and Y chromosomes (including gene content, the pseudoautosomal regions, and X chromosome inactivation), discuss how sex chromosomes have been ignored in Genome-wide Association Studies (GWAS) of cardiovascular diseases, and discuss genetics influencing development of cardiovascular risk factors and atherosclerosis with particular attention to carotid intima-medial thickness, and coronary arterial calcification based on sex-specific studies.
Cardiovascular disease (CVD) has been seen as a men's disease for decades, however it is more common in women than in men. It is generally assumed in medicine that the effects of the major risk factors (RF) on CVD outcomes are the same in women as in men. Recent evidence has emerged that recognizes new, potentially independent, CVD RF exclusive to women. In particular, common disorders of pregnancy, such as gestational hypertension and diabetes, as well as frequently occurring endocrine disorders in women of reproductive age (e.g.
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