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Optimal use of guideline-directed medical therapy (GDMT) can prevent hospitalization and mortality among patients with heart failure (HF). We aimed to assess the prevalence of GDMT use for HF across geographic regions and country-income levels. We systematically reviewed observational studies (published between January 2010 and October 2020) involving patients with HF with reduced ejection fraction. We conducted random-effects meta-analyses to obtain summary estimates. We included 334 studies comprising 1,507,849 patients (31% female). The majority (82%) of studies were from high-income countries, with Europe (45%) and the Americas (33%) being the most represented regions, and Africa (1%) being the least. Overall prevalence of GDMT use was 80% (95% CI 78%–81%) for β-blockers, 82% (80%–83%) for renin–angiotensin-system inhibitors, and 41% (39%–43%) for mineralocorticoid receptor antagonists. We observed an exponential increase in GDMT use over time after adjusting for country-income levels (p < 0.0001), but significant gaps persist in low- and middle-income countries. Multi-level interventions are needed to address health-system, provider, and patient-level barriers to GDMT use.

Abstract Objectives There is conflicting evidence around the role of sex hormones with cardiovascular outcomes. The aim of this study was to examine the association of sex hormones with the risk of myocardial infarction (MI) in pre- and post-menopausal women, and men in the UK Biobank. Methods The UK Biobank is a prospective population-based cohort study, that recruited over 500,000 (aged 40–69 years) women and men between 2006 and 2010. Sex specific cox regression models, estimating hazard ratios (HRs) and women to men ratio of HRs (RHR) with respective 95% confidence intervals (CI), were used to model the association of sex hormones [oestrogen, testosterone, oestrogen: testosterone (O/T) ratio, sex hormone–binding globulin (SHBG) and the free androgen index (FAI)], measured at study baseline, with incident MI for women and men. Results Data were from 479,797 participants [264,282 (55.1%) women] without a history of MI at study baseline. Over 12.5 years of follow-up, there were 4,908 MI events in women and 10,517 in men. Neither oestrogen nor testosterone were associated with MI in women and men after multiple adjustment. For men, but not women, a unit higher log-transformed O/T ratio was associated with a lower risk of MI 0.79 (0.65, 0.95) after adjustment for traditional CVD risk factors. The corresponding women to men RHR (95% CI) was 1.24 (0.99, 1.56). Higher SHBG (per unit) was also associated with a lower risk of MI in men 0.94 (0.89, 0.99), and not in women 1.02 (0.95, 1.09) after multiple adjustment, the corresponding women to men RHR (95% CI) was 1.09 (1.00, 1.18). Higher FAI was associated with a higher risk of MI in men 1.09 (1.02, 1.15), though not in women 0.97 (0.92, 1.02), the corresponding women to men RHR was 0.89 (0.82, 0.97). Finally, there were differential effects in the association of SHBG and FAI between pre- and post-menopausal women. Conclusions A higher O/T ratio was associated with a lower risk of MI, and a higher FAI with a higher risk of MI after adjustment for CVD risk factors in men, but not in women. Thus, hormone ratios, rather than each alone, may play an important role in modulating the effect of MI.

Abstract Sex and gender are fundamental aspects of health and wellbeing. Yet many research studies fail to consider sex or gender differences, and even when they do this is often limited to merely cataloguing such differences in the makeup of study populations. The evidence on sex and gender differences is thus incomplete in most areas of medicine. This article presents a roadmap for the systematic conduct of sex- and gender-disaggregated health research. We distinguish three phases: the exploration of sex and gender differences in disease risk, presentation, diagnosis, treatment, and outcomes; explaining any found differences by revealing the underlying mechanisms; and translation of the implications of such differences to policy and practice. For each phase, we provide critical methodological considerations and practical examples are provided, taken primarily from the field of cardiovascular disease. We also discuss key overarching themes and terminology that are at the essence of any study evaluating the relevance of sex and gender in health. Here, we limit ourselves to binary sex and gender in order to produce a coherent, succinct narrative. Further disaggregation by sex and gender separately and which recognises intersex, non-binary, and gender-diverse identities, as well as other aspects of intersectionality, can build on this basic minimum level of disaggregation. We envision that uptake of this roadmap, together with wider policy and educational activities, will aid researchers to systematically explore and explain relevant sex and gender differences in health and will aid educators, clinicians, and policymakers to translate the outcomes of research in the most effective and meaningful way, for the benefit of all.

Background: Globally, cardiovascular disease (CVD) remains the leading cause of mortality and disability, with hypertension being the single most important modifiable risk factor. Hypertension is responsible for about 18% of global deaths from CVD, of which African regions are disproportionately affected, especially sub-Saharan Africa. This study assessed the burden of major CVD subtypes attributable to hypertension in Nigeria. Methods: The population attributable fractions (PAF) for myocardial infarction, all strokes, ischaemic stroke and intracerebral haemorrhagic stroke attributable to hypertension in Nigeria were calculated using published results from the INTERHEART and INTERSTROKE studies and prevalence estimates of hypertension in Nigeria. PAF estimates were obtained for age, sex, and geopolitical zones. Results: Overall, hypertension contributed to 13.2% of all myocardial infarctions and 24.6% of all strokes, including 21.6% of all ischaemic strokes and 33.1% of all intracerebral haemorrhagic strokes. Among men aged ≤55 years, the PAF for myocardial infarction ranged from 11.7% (North-West) to 14.6% (South-East), while in older men, it spanned 9.2% (North-West) to 11.9% (South-East). Among women aged ≤65 years, PAF varied from 18.6% (South-South) to 20.8% (South-East and North-Central), and among women aged >65 years, it ranged from 10.4% (South-South) to 12.7% (South-East). Conclusion: Hypertension is a key contributor to the burden of CVD in Nigeria. Understanding the burden of hypertension in the Nigerian population overall and key subgroups is crucial to developing and implementing contextualised health policies to reduce the burden of CVD. Public health interventions and policies centred on hypertension will play a critical role in potentially alleviating the burden of cardiovascular diseases (CVD) in Nigeria.

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC‐CVD (European Prospective Investigation Into Cancer and Nutrition‐Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC‐CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow‐up of 12.6 years (interquartile range, 11.8–13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07–1.12) for stroke, 1.09 (95% CI, 1.06–1.13) for ischemic stroke, 1.10 (95% CI, 1.04–1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08–1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84–1.20) for subarachnoid hemorrhage. When using 2‐sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Background: Sex differences in the primary prevention of cardiovascular diseases (CVD) have been shown, but the evidence is mixed and fragmented. In this study, we assessed sex differences in cardiovascular risk factors assessment, risk factor levels, treatment, and meeting of treatment targets, within a Dutch primary care setting. Methods: Data were obtained from individuals aged 40 to 70 years old, without prior CVD, registered during the entire year in 2018 at one of the 51 general practices participating in the Julius General Practitioner’s Network (JGPN). History of CVD was defined based on the International Classification of Primary Care (ICPC). Linear and Poisson regressions were used to investigate sex differences in risk factor assessment, risk factor levels, treatment, and meeting of treatment targets. Results: We included 83,903 individuals (50% women). With the exception of glycated hemoglobin (HbA1c), all risk factors for CVD were more often measured in women than in men. Lipid measurements and body mass index values were higher in women, while blood pressure (BP) and HbA1c levels were higher in men, along with estimated glomerular filtration rate (eGFR) levels. Among individuals with elevated BP or cholesterol levels, no sex difference was observed in the prescription of antihypertensive medications (RR 1.00, 95% CI: 0.94–1.06) but women were less likely than men to receive lipid-lowering medications (RR 0.87, 95% CI: 0.79–0.95). Among treated individuals, women were more likely than men to meet adequate levels of blood pressure (RR 1.17, 95% CI: 1.09–1.25) and less likely to meet target levels of cholesterol (RR 0.90, 95% CI: 0.83–0.98). Conclusion: While women were more likely to have their CVD risk factors measured, they were less likely to be prescribed lipid-lowering medications and to meet target levels. When treated, men were less likely to achieve adequate blood pressure control.

Abstract Although male Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) patients have higher Intensive Care Unit (ICU) admission rates and a worse disease course, a comprehensive analysis of female and male ICU survival and underlying factors such as comorbidities, risk factors, and/or anti-infection/inflammatory therapy administration is currently lacking. Therefore, we investigated the association between sex and ICU survival, adjusting for these and other variables. In this multicenter observational cohort study, all patients with SARS-CoV-2 pneumonia admitted to seven ICUs in one region across Belgium, The Netherlands, and Germany, and requiring vital organ support during the first pandemic wave were included. With a random intercept for a center, mixed-effects logistic regression was used to investigate the association between sex and ICU survival. Models were adjusted for age, Acute Physiology and Chronic Health Evaluation II (APACHE II) score, comorbidities, and anti-infection/inflammatory therapy. Interaction terms were added to investigate effect modifications by sex with country and sex with obesity. A total of 551 patients (29% were females) were included. Mean age was 65.4 ± 11.2 years. Females were more often obese and smoked less frequently than males (p-value 0.001 and 0.042, respectively). APACHE II scores of females and males were comparable. Overall, ICU mortality was 12% lower in females than males (27% vs 39% respectively, p-value 0.23 and 0.84, respectively). ICU survival in female SARS-CoV-2 patients was higher than in male patients, independent of age, disease severity, smoking, obesity, comorbidities, anti-infection/inflammatory therapy, and country. Sex-specific biological mechanisms may play a role, emphasizing the need to address diversity, such as more sex-specific prediction, prognostic, and therapeutic approach strategies.

Life expectancy (LE) depends on the wider determinants of health, many of which have gendered effects worldwide. Therefore, this study aimed to investigate whether gender equality was associated with LE for women and men and the gender gap in LE across the globe. Gender equality in 156 countries was estimated using a modified global gender gap index (mGGGI), based on the index developed by the World Economic Forum between 2010 and 2021. Linear regression was used to investigate the association between the mGGGI and its economic, political, and education subindices and the gender gap in LE and women and men’s LE. Overall, the mGGGI increased from 58% in 2010 to 62% in 2021. Globally, changes in the mGGGI and its economic and political subindexes were not associated with changes in the gender gap in LE or with LE for women and men between 2010 and 2020. Improvements in gender equality in education were associated with a longer LE for women and men and widening of the gender gap in LE. In 2021, each 10% increase in the mGGGI was associated with a 4.3-month increase in women’s LE and a 3.5-month increase in men’s LE, and thus with an 8-month wider gender gap. However, the direction and magnitude of these associations varied between regions. Each 10% increase in the mGGGI was associated with a 6-month narrower gender gap in high-income countries, and a 13- and 16-month wider gender gap in South and Southeast Asia and Oceania, and in Sub-Saharan Africa, respectively. Globally, greater gender equality is associated with longer LE for both women and men and a widening of the gender gap in LE. The variation in this association across world regions suggests that gender equality may change as countries progress towards socioeconomic development and gender equality.

Abstract Background Women with type 2 diabetes are disproportionally affected by macrovascular complications; we here investigated whether this is also the case for microvascular complications and retinal microvascular measures. Methods In a population-based cohort study of individuals aged 40–75 years (n = 3410; 49% women, 29% type 2 diabetes (oversampled by design)), we estimated sex-specific associations, and differences therein, of (pre)diabetes (reference: normal glucose metabolism), and of continuous measures of glycemia with microvascular complications and retinal measures (nephropathy, sensory neuropathy, and retinal arteriolar and venular diameters and dilatation). Sex differences were analyzed using regression models with interaction terms (i.e. sex-by- (pre)diabetes and sex-by-glycemia) and were adjusted for potential confounders. Results Men with type 2 diabetes (but not those with prediabetes) compared to men with normal glucose metabolism, (and men with higher levels of glycemia), had significantly higher prevalences of nephropathy (odds ratio: 1.58 95% CI (1.01;2.46)) and sensory neuropathy (odds ratio: 2.46 (1.67;3.63)), larger retinal arteriolar diameters (difference: 4.29 µm (1.22;7.36)) and less retinal arteriolar dilatation (difference: − 0.74% (− 1.22; − 0.25)). In women, these associations were numerically in the same direction, but generally not statistically significant (odds ratios: 1.71 (0.90;3.25) and 1.22 (0.75;1.98); differences: 0.29 µm (− 3.50;4.07) and: − 0.52% (− 1.11;0.08), respectively). Interaction analyses revealed no consistent pattern of sex differences in the associations of either prediabetes or type 2 diabetes or glycemia with microvascular complications or retinal measures. The prevalence of advanced-stage complications was too low for evaluation. Conclusions Our findings show that women with type 2 diabetes are not disproportionately affected by early microvascular complications.

Abstract Background Sex differences in major cardiovascular risk factors for incident (fatal or non-fatal) all-cause dementia were assessed in the UK Biobank. The effects of these risk factors on all-cause dementia were explored by age and socioeconomic status (SES). Methods Cox proportional hazards models were used to estimate hazard ratios (HRs) and women-to-men ratio of HRs (RHR) with 95% confidence intervals (CIs) for systolic blood pressure (SBP) and diastolic blood pressure (DBP), smoking, diabetes, adiposity, stroke, SES and lipids with dementia. Poisson regression was used to estimate the sex-specific incidence rate of dementia for these risk factors. Results 502,226 individuals in midlife (54.4% women, mean age 56.5 years) with no prevalent dementia were included in the analyses. Over 11.8 years (median), 4068 participants (45.9% women) developed dementia. The crude incidence rates were 5.88 [95% CI 5.62–6.16] for women and 8.42 [8.07–8.78] for men, per 10,000 person-years. Sex was associated with the risk of dementia, where the risk was lower in women than men (HR = 0.83 [0.77–0.89]). Current smoking, diabetes, high adiposity, prior stroke and low SES were associated with a greater risk of dementia, similarly in women and men. The relationship between blood pressure (BP) and dementia was U-shaped in men but had a dose-response relationship in women: the HR for SBP per 20 mmHg was 1.08 [1.02–1.13] in women and 0.98 [0.93–1.03] in men. This sex difference was not affected by the use of antihypertensive medication at baseline. The sex difference in the effect of raised BP was consistent for dementia subtypes (vascular dementia and Alzheimer’s disease). Conclusions Several mid-life cardiovascular risk factors were associated with dementia similarly in women and men, but not raised BP. Future bespoke BP-lowering trials are necessary to understand its role in restricting cognitive decline and to clarify any sex difference.

IntroductionGlobally, women with dementia have a higher disease burden than men with dementia. In addition, women with diabetes especially are at higher risk for cognitive impairment and dementia compared to men with diabetes. Differences in the influence of diabetes on the cerebral vasculature and brain structure may contribute to these sex-specific differences. We examined sex-specific patterns in the relationship between diabetes and brain structure, as well as diabetes and cognitive function.MethodsIn total, 893 patients [age 79 ± 6.6 years, 446 (50%) women] from the Amsterdam Ageing Cohort with available data on brain structures (assessed by an MRI or CT scan) and cognitive function were included. All patients underwent a thorough standardized clinical and neuropsychological assessment (including tests on memory, executive functioning, processing speed, language). Brain structure abnormalities were quantified using visual scales.ResultsCross-sectional multivariable regression analyses showed that diabetes was associated with increased incidence of cerebral lacunes and brain atrophy in women (OR 2.18 (1.00–4.72) but not in men. Furthermore, diabetes was associated with decreased executive function, processing speed and language in women [B −0.07 (0.00–0.13), −0.06 (0.02–0.10) and −0.07 (0.01–0.12) resp.] but not in men.ConclusionsDiabetes is related to increased risk of having lacunes, brain atrophy and impaired cognitive function in women but not in men. Further research is required to understand the time trajectory leading up to these changes and to understand the mechanisms behind them in order to improve preventive health care for both sexes.

Abstract Background Due to a critical shortage of available kidney grafts, most patients with Stage 5 Chronic Kidney Disease (CKD5) require bridging dialysis support. It remains unclear whether treatment by different dialysis modalities changes the selection and/or preparation of a potential transplant candidate. Therefore, we assessed whether the likelihood of receiving kidney transplant (both living or deceased kidney donors) differs between haemodialysis (HD) and online haemodiafiltration (HDF) in patients with CKD5D. Methods Individual participant data from four randomised controlled trials comparing online HDF with HD were used. Information on kidney transplant was obtained during follow-up. The likelihood of receiving a kidney transplant was compared between HD and HDF, and evaluated across different subgroups: age, sex, diabetes, history of cardiovascular disease, albumin, dialysis vintage, fistula, and level of convection volume standardized to body surface area. Hazard ratios (HRs), with corresponding 95% confidence intervals (95% CI), comparing the effect of online HDF versus HD on the likelihood of receiving a kidney transplant, were estimated using Cox proportional hazards models with a random effect for study. Results After a median follow-up of 2.5 years (Q1 to Q3: 1.9–3.0), 331 of the 1620 (20.4%) patients with CKD5D received a kidney transplant. This concerned 22% (n = 179) of patients who were treated with online HDF compared with 19% (n = 152) of patients who were treated with HD. No differences in the likelihood of undergoing a kidney transplant were found between the two dialysis modalities in both the crude analyse (HR: 1.07, 95% CI: 0.86–1.33) and adjusted analysis for age, sex, diabetes, cardiovascular history, albumin, and creatinine (HR: 1.15, 95%-CI: 0.92–1.44). There was no evidence for a differential effect across subgroups based on patient- and disease-characteristics nor in different categories of convection volumes. Conclusions Treatment with HD and HDF does not affect the selection and/or preparation of CKD5D patients for kidney transplant given that the likelihood of receiving a kidney transplant does not differ between the dialysis modalities. These finding persisted across a variety of subgroups differing in patient and disease characteristics and is not affected by the level of convection volume delivered during HDF treatment sessions.

The associations of plasma levels of hemostatic factors, other than fibrinogen, with risks of cardiovascular disease (CVD) and all-cause mortality are not well defined. In two phases of the Glasgow MONICA study, we assayed coagulation factors (VII, VIII, IX, and von Willebrand factor), coagulation inhibitors (antithrombin, protein C, protein S), coagulation activation markers (prothrombin fragment 1 + 2, thrombin–antithrombin complexes, D-dimer), and the fibrinolytic factors, tissue plasminogen activator (t-PA) antigen and plasminogen activator inhibitor type 1. Over 15 to 20 years, we followed up between 382 and 1,123 men and women aged 30 to 74 years, without baseline CVD, for risks of CVD and mortality. Age- and sex-adjusted hazard ratios (HRs) for CVD (top third vs bottom third) were significant only for factor VIII (1.30; 95% confidence interval [CI], 1.06–1.58) and factor IX (1.18; 95% CI, 1.01–1.39); these HRs were attenuated by further adjustment for CVD risk factors: 1.17 (95% CI, 0.94–1.46) and 1.07 (95% CI, 0.92–1.25), respectively. In contrast, factor VIII (HR, 1.63; 95% CI, 1.35–1.96), D-dimer (HR, 2.34; 95% CI, 1.26–4.35), and t-PA (HR, 2.81; 95% CI, 1.43–5.54) were strongly associated with mortality after full risk factor adjustment. Further studies, including meta-analyses, are required to assess the associations of these hemostatic factors with the risks of stroke and heart disease and causes of mortality.

Abstract Aims/hypothesis Previous meta-analyses have suggested that diabetes confers a greater excess risk of coronary heart disease, stroke, vascular dementia, and heart failure in women compared to men. While the underlying mechanism that explains such greater excess risk is unknown, in the current meta-analysis we hypothesized that we would find a similar sex difference in the relationship between diabetes and peripheral arterial disease (PAD). Methods PubMed MEDLINE, the Cochrane Database of Systematic Reviews, and Embase were systematically searched for prospective population-based cohort studies, with no restriction on publication date, language, or country. We included studies that reported the relative risk (RR), and its variability, for incident PAD associated with diabetes in both sexes. We excluded studies that did not adjust at least for age, and in which participants had pre-existing PAD. In cases where sex-specific results were not reported, study authors were contacted. Random-effects meta-analyses with inverse variance weighting were used to obtain summary sex-specific RRs and the women: men ratio of RRs for PAD. The Newcastle–Ottawa scale was used to assess study quality. Results Data from seven cohorts, totalling 2071,260 participants (49.8% women), were included. The relative risk for incident PAD associated with diabetes compared with no diabetes was 1.96 (95% CI 1.29–2.63) in women and 1.84 (95% CI 1.29–2.86) in men, after adjusting for potential confounders. The multiple-adjusted RR ratio was 1.05 (95% CI 0.90–1.22), with virtually no heterogeneity between studies (I2 = 0%). All studies scored 6–8, on the Newcastle–Ottawa scale of 0–9, indicating good quality. Eleven of the 12 studies that met review inclusion criteria did not report sex-specific relative risk, and these data were collected through direct correspondence with the study authors. Conclusion/interpretation Consistent with other studies, we found evidence that diabetes is an independent risk factor for PAD. However, in contrast to similar studies of other types of cardiovascular disease, we did not find evidence that diabetes confers a greater excess risk in women compared to men for PAD. More research is needed to explain this sex differential between PAD and other forms of CVD, in the sequelae of diabetes. In addition, we found that very few studies reported the sex-specific relative risk for the association between diabetes and PAD, adding to existing evidence for the need for improved reporting of sex-disaggregated results in cardiovascular disease research.

Abstract Diabetes is a strong risk factor for vascular disease. There is compelling evidence that the relative risk of vascular disease associated with diabetes is substantially higher in women than men. The mechanisms that explain the sex difference have not been identified. However, this excess risk could be due to certain underlying biological differences between women and men. In addition to other cardiometabolic pathways, sex differences in body anthropometry and patterns of storage of adipose tissue may be of particular importance in explaining the sex differences in the relative risk of diabetes-associated vascular diseases. Besides biological factors, differences in the uptake and provision of health care could also play a role in women’s greater excess risk of diabetic vascular complications. In this review, we will discuss the current knowledge regarding sex differences in both biological factors, with a specific focus on sex differences adipose tissue, and in health care provided for the prevention, management, and treatment of diabetes and its vascular complications. While progress has been made towards understanding the underlying mechanisms of women’s higher relative risk of diabetic vascular complications, many uncertainties remain. Future research to understanding these mechanisms could contribute to more awareness of the sex-specific risk factors and could eventually lead to more personalized diabetes care. This will ensure that women are not affected by diabetes to a greater extent and will help to diminish the burden in both women and men.

Background Breastfeeding has been robustly linked to reduced maternal risk of breast cancer, ovarian cancer, and type 2 diabetes. We herein systematically reviewed the published evidence on the association of breastfeeding with maternal risk of cardiovascular disease (CVD) outcomes. Methods and Results Our systematic search of PubMed and Web of Science of articles published up to April 16, 2021, identified 8 relevant prospective studies involving 1 192 700 parous women (weighted mean age: 51.3 years at study entry, 24.6 years at first birth; weighted mean number of births: 2.3). A total of 982 566 women (82%) reported having ever breastfed (weighted mean lifetime duration of breastfeeding: 15.6 months). During a weighted median follow‐up of 10.3 years, 54 226 CVD, 26 913 coronary heart disease, 30 843 stroke, and 10 766 fatal CVD events were recorded. In a random‐effects meta‐analysis, the pooled multivariable‐adjusted hazard ratios comparing parous women who ever breastfed to those who never breastfed were 0.89 for CVD (95% CI, 0.83–0.95; I2=79.4%), 0.86 for coronary heart disease (95% CI, 0.78–0.95; I2=79.7%), 0.88 for stroke (95% CI, 0.79–0.99; I2=79.6%), and 0.83 for fatal CVD (95% CI, 0.76–0.92; I2=47.7%). The quality of the evidence assessed with the Grading of Recommendations Assessment, Development, and Evaluation tool ranged from very low to moderate, which was mainly driven by high between‐studies heterogeneity. Strengths of associations did not differ by mean age at study entry, median follow‐up duration, mean parity, level of adjustment, study quality, or geographical region. A progressive risk reduction of all CVD outcomes with lifetime durations of breastfeeding from 0 up to 12 months was found, with some uncertainty about shapes of associations for longer durations. Conclusions Breastfeeding was associated with reduced maternal risk of CVD outcomes.

Background: Clustering of vascular risk factors, i.e., the co-existence of two or more risk factors, has been associated with a higher risk of cardiovascular disease (CVD) in the general population. This study aims to firstly, examine patterns of clustering of major cardiovascular risk factors in high-risk patients and their relation with the risk of recurrent cardiovascular disease and all-cause mortality. Secondly, to assess which combinations are associated with the highest risk of CVD and all-cause mortality and to study population attributable fractions. Methods: A total of 12,616 patients from the Utrecht Cardiovascular Cohort – Second Manifestations of ARTerial diseases (UCC-SMART) study consisting of patients with or a high risk to develop cardiovascular disease were studied. We constructed sixteen clusters based on four individual modifiable risk factors (hypertension, dyslipidemia, current smoking, overweight). Patients were followed from September 1997 to March 2017. Cox proportional hazard models were used to compute adjusted hazard ratios for CVD risk and all-cause mortality and 95% confidence intervals for clusters, with patients without any risk factor as reference group. The population attributable fractions (PAFs) were calculated. Subgroup analyses were conducted by age and sex. Results: During a mean follow-up period of 8.0 years, 1836 CVD events were registered. The prevalence of patients with zero, one, two, three, and four risk factors was 1.4, 11.4, 32.0, 44.8 and 10.4%. The corresponding hazard ratios (HR) for CVD risk and all-cause mortality were 1.65 (95% CI 0.77; 3.54) for one risk factor, 2.61 (1.24; 5.50) for two, 3.25 (1.55; 6.84) for three, and 3.74 (1.77; 7.93) for four risk factors, with patients without any risk factor as reference group. The PAFs were 6.9, 34.0, 50.1 and 22.2%, respectively. The smoking-hypertension-dyslipidemia combination was associated with the highest HR: 4.06 (1.91; 8.63) and the hypertension-dyslipidemia combination with the highest PAF: 37.1%. Conclusion: Clusters including smoking and hypertension contributed to the highest risk of CVD and all-cause mortality. This study confirms that risk factor clustering is common among patients at high-risk for CVD and is associated with an increased risk of CVD and all-cause mortality.

BackgroundInsight in sex disparities in the detection of cardiovascular risk factors and diabetes-related complications may improve diabetes care. The aim of this systematic review is to study whether sex disparities exist in the assessment of cardiovascular risk factors and screening for diabetes-related complications.MethodsPubMed was systematically searched up to April 2020, followed by manual reference screening and citations checks (snowballing) using Google Scholar. Observational studies were included if they reported on the assessment of cardiovascular risk factors (HbA1c, lipids, blood pressure, smoking status, or BMI) and/or screening for nephropathy, retinopathy, or performance of feet examinations, in men and women with diabetes separately. Studies adjusting their analyses for at least age, or when age was considered as a covariable but left out from the final analyses for various reasons (i.e. backward selection), were included for qualitative analyses. No meta-analyses were planned because substantial heterogeneity between studies was expected. A modified Newcastle-Ottawa Quality Assessment Scale for cohort studies was used to assess risk of bias.ResultsOverall, 81 studies were included. The majority of the included studies were from Europe or North America (84%).The number of individuals per study ranged from 200 to 3,135,019 and data were extracted from various data sources in a variety of settings. Screening rates varied considerably across studies. For example, screening rates for retinopathy ranged from 13% to 90%, with half the studies reporting screening rates less than 50%. Mixed findings were found regarding the presence, magnitude, and direction of sex disparities with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, with some evidence suggesting that women, compared with men, may be more likely to receive retinopathy screening and less likely to receive foot exams.ConclusionOverall, no consistent pattern favoring men or women was found with regard to the assessment of cardiovascular risk factors and screening for diabetes-related complications, and screening rates can be improved for both sexes.

Introduction: Pharmacological treatment is an important component of secondary prevention in acute coronary syndrome (ACS) survivors. However, adherence to medication regimens is often suboptimal, reducing the effectiveness of treatment. It has been suggested that sex influences adherence to cardiovascular medication, but results differ across studies, and a systematic overview is lacking.Methods: We performed a systematic search of PubMed and EMBASE on 16 October 2019. Studies that reported sex-specific adherence for one or more specific medication classes for ACS patients were included. Odds ratios, or equivalent, were extracted per medication class and combined using a random effects model.Results: In total, we included 28 studies of which some had adherence data for more than one medication group. There were 7 studies for angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) (n = 100,909, 37% women), 8 studies for antiplatelet medication (n = 37,804, 27% women), 11 studies for beta-blockers (n = 191,339, 38% women), and 17 studies for lipid-lowering medication (n = 318,837, 35% women). Women were less adherent to lipid-lowering medication than men (OR = 0.87, 95% CI 0.82–0.92), but this sex difference was not observed for antiplatelet medication (OR = 0.95, 95% CI 0.83–1.09), ACEIs/ARBs (OR = 0.95, 95% CI 0.78–1.17), or beta-blockers (OR = 0.97, 95% CI 0.86–1.11).Conclusion: Women with ACS have poorer adherence to lipid-lowering medication than men with the same condition. There are no differences in adherence to antiplatelet medication, ACEIs/ARBs, and beta-blockers between women and men with ACS.

Background Sex differences in the management of cardiovascular disease have been reported in secondary care. We conducted a systematic review with meta‐analysis of systematically investigated sex differences in cardiovascular medication prescription among patients at high risk or with established cardiovascular disease in primary care. Methods and Results PubMed and Embase were searched between 2000 and 2019 for observational studies reporting on the sex‐specific prevalence of aspirin, statins, and antihypertensive medication prescription, including beta blockers, calcium channel blockers, angiotensin‐converting enzyme inhibitors, and diuretics, in primary care. Random effects meta‐analysis was used to obtain pooled women‐to‐men prevalence ratios for each cardiovascular medication prescription. Metaregression models assessed the impact of age and year on the findings. A total of 43 studies were included, involving 2 264 600 participants (28% women) worldwide. Participants’ mean age ranged from 51 to 76 years. The pooled prevalence of cardiovascular medication prescription for women was 41% for aspirin, 60% for statins, and 68% for any antihypertensive medications. Corresponding rates for men were 56%, 63%, and 69% respectively. The pooled women‐to‐men prevalence ratios were 0.81 (95% CI, 0.72–0.92) for aspirin, 0.90 (95% CI, 0.85–0.95) for statins, and 1.01 (95% CI, 0.95–1.08) for any antihypertensive medications. Women were less likely to be prescribed angiotensin‐converting enzyme inhibitors (0.85; 95% CI, 0.81–0.89) but more likely with diuretics (1.27; 95% CI, 1.17–1.37). Mean age, mean age difference between the sexes, and year of study had no significant impact on findings. Conclusions Sex differences in the prescription of cardiovascular medication exist among patients at high risk or with established cardiovascular disease in primary care, with a lower prevalence of aspirin, statins, and angiotensin‐converting enzyme inhibitors prescription in women and a lower prevalence of diuretics prescription in men.

Background Timely recognition of patients with acute coronary syndromes (ACS) is important for successful treatment. Previous research has suggested that women with ACS present with different symptoms compared with men. This review assessed the extent of sex differences in symptom presentation in patients with confirmed ACS. Methods and Results A systematic literature search was conducted in PubMed, Embase, and Cochrane up to June 2019. Two reviewers independently screened title‐abstracts and full‐texts according to predefined inclusion and exclusion criteria. Methodological quality was assessed using the Newcastle‐Ottawa Scale. Pooled odds ratios (OR) with 95% CI of a symptom being present were calculated using aggregated and cumulative meta‐analyses as well as sex‐specific pooled prevalences for each symptom. Twenty‐seven studies were included. Compared with men, women with ACS had higher odds of presenting with pain between the shoulder blades (OR 2.15; 95% CI, 1.95–2.37), nausea or vomiting (OR 1.64; 95% CI, 1.48–1.82) and shortness of breath (OR 1.34; 95% CI, 1.21–1.48). Women had lower odds of presenting with chest pain (OR 0.70; 95% CI, 0.63–0.78) and diaphoresis (OR 0.84; 95% CI, 0.76–0.94). Both sexes presented most often with chest pain (pooled prevalences, men 79%; 95% CI, 72–85, pooled prevalences, women 74%; 95% CI, 72–85). Other symptoms also showed substantial overlap in prevalence. The presence of sex differences has been established since the early 2000s. Newer studies did not materially change cumulative findings. Conclusions Women with ACS do have different symptoms at presentation than men with ACS, but there is also considerable overlap. Since these differences have been shown for years, symptoms should no longer be labeled as “atypical” or “typical.”

Abstract Background Pregnancy and pregnancy loss may be linked to cardiovascular disease (CVD). However, the evidence is still inconsistent, especially in East Asians, whose reproductive patterns differ importantly from those in the West. We examined the associations of pregnancy, miscarriage, induced abortion, and stillbirth with CVD incidence among Chinese women. Methods In 2004–2008, the nationwide China Kadoorie Biobank recruited 302,669 women aged 30–79 years from ten diverse localities. During 7 years of follow-up, 43,968 incident cases of circulatory disease, 14,440 of coronary heart disease, and 19,925 of stroke (including 11,430 ischaemic and 2170 haemorrhagic strokes), were recorded among 289,573 women without prior CVD at baseline. Cox regression yielded multiple adjusted hazard ratios (HRs) for CVD risks associated with pregnancy outcomes. Results Overall, 99% of women had been pregnant, and among them 10%, 53%, and 7% reported having a history of miscarriage, induced abortion, and stillbirth, respectively. Each additional pregnancy was associated with an adjusted HR of 1.03 (95% confidence interval, CI: 1.02; 1.04) for circulatory disease. A history of miscarriage, induced abortion, and stillbirth, respectively, were associated with adjusted HRs of 1.04 (1.01; 1.07), 1.04 (1.02; 1.07), and 1.07 (1.03; 1.11) for circulatory disease. The relationship was stronger with recurrent pregnancy loss; adjusted HRs for each additional loss being 1.04 (1.00; 1.09) for miscarriage, 1.02 (1.01; 1.04) for induced abortion, and 1.04 (1.00; 1.08) for stillbirth. Conclusions Among Chinese women, increases in pregnancy, and a history and recurrence of miscarriage, induced abortion, and stillbirth are each associated with a higher risk of CVD.

BackgroundThere are substantial differences in the distribution of adipose tissue between women and men. We assessed the sex‐specific relationships and their differences between measures of general and central adiposity and the risk of incident myocardial infarction (MI). Methods and ResultsBetween 2006 and 2010, the UK Biobank recruited over 500 000 participants aged 40 to 69 years across the United Kingdom. During 7 years of follow‐up, 5710 cases of MI (28% women) were recorded among 265 988 women and 213 622 men without a history of cardiovascular disease at baseline. Cox regression models yielded adjusted hazard ratios for MI associated with body mass index, waist circumference, waist‐to‐hip ratio, and waist‐to‐height ratio. There was an approximate log‐linear relationship between measures of general and central adiposity and the risk of MI in both sexes. A 1‐SD higher in body mass index, waist circumference, waist‐to‐hip ratio, and waist‐to‐height ratio, respectively, were associated with hazard ratios (confidence intervals) for MI of 1.22 (1.17; 1.28), 1.35 (1.28; 1.42), 1.49 (1.39; 1.59), and 1.34 (1.27; 1.40) in women and of 1.28 (1.23; 1.32), 1.28 (1.23; 1.33), 1.36 (1.30; 1.43), and 1.33 (1.28; 1.38) in men. The corresponding women‐to‐men ratios of hazard ratios were 0.96 (0.91; 1.02), 1.07 (1.00; 1.14), 1.15 (1.06; 1.24), and 1.03 (0.97; 1.09). ConclusionsAlthough general and central adiposity measures each have profound deleterious effects on the risk of MI in both sexes, a higher waist circumference and waist‐to‐hip ratio conferred a greater excess risk of MI in women than in men. Waist‐to‐hip ratio was more strongly associated with the risk of MI than body mass index in both sexes, especially in women.

BackgroundBreastfeeding confers substantial benefits to child health and has also been associated with lower risk of maternal cardiovascular diseases (CVDs) in later life. However, the evidence on the effects of CVD is still inconsistent, especially in East Asians, in whom the frequency and duration of breastfeeding significantly differ from those in the West. Methods and ResultsIn 2004–2008, the nationwide China Kadoorie Biobank recruited 0.5 million individuals aged 30 to 79 years from 10 diverse regions across China. During 8 years of follow‐up, 16 671 incident cases of coronary heart disease and 23 983 cases of stroke were recorded among 289 573 women without prior CVD at baseline. Cox regression yielded adjusted hazard ratios (HRs) and 95% CIs for incident CVD by breastfeeding. Overall, ≈99% of women had given birth, among whom 97% reported a history of breastfeeding, with a median duration of 12 months per child. Compared with parous women who had never breastfed, ever breastfeeding was associated with a significantly lower risk of CVD, with adjusted HRs of 0.91 (95% CI, 0.84–0.99) for coronary heart disease and 0.92 (95% CI, 0.85–0.99) for stroke. Women who had breastfed for ≥24 months had an 18% (HR, 0.82; 0.77–0.87) lower risk of coronary heart disease and a 17% (HR, 0.83; 0.79–0.87) lower risk of stroke compared with women who had never breastfed. Among women who ever breastfed, each additional 6 months of breastfeeding per child was associated with an adjusted HR of 0.96 (95% CI, 0.94–0.98) for coronary heart disease and 0.97 (95% CI, 0.96–0.98) for stroke. ConclusionsAmong Chinese women, a history of breastfeeding was associated with an ≈10% lower risk of CVD in later life and the magnitude of the inverse association was stronger among those with a longer duration of breastfeeding.

BackgroundCoronary heart disease and peripheral arterial disease (PAD) affect different vascular territories. Supplementing baseline findings with assays from stored serum, we compared their 20‐year predictors. Methods and ResultsWe randomly recruited 15 737 disease‐free men and women aged 30 to 75 years across Scotland between 1984 and 1995 and followed them through 2009 for death and hospital diagnoses. Of these, 3098 developed coronary heart disease (19.7%), and 499 PAD (3.2%). Hazard ratios for 45 variables in the Cox model were adjusted for age and sex and for factors in the 2007 ASSIGN cardiovascular risk score. Forty‐four of them were entered into parsimonious predictive models, tested by c‐statistics and net reclassification improvements. Many hazard ratios diminished with adjustment and parsimonious modeling, leaving significant survivors. The hazard ratios were mostly higher in PAD. New parsimonious models increased the c‐statistic and net reclassification improvements over ASSIGN variables alone but varied in their components and ranking. Coronary heart disease and PAD shared 7 of the 9 factors from ASSIGN: age, sex, family history, socioeconomic status, diabetes mellitus, tobacco smoking, and systolic blood pressure (but neither total nor high‐density lipoprotein cholesterol); plus 4 new ones: NT‐pro‐BNP, cotinine, high‐sensitivity C‐reactive protein, and cystatin‐C. The highest ranked hazard ratios for continuous factors in coronary heart disease were those for age, total cholesterol, high‐sensitivity troponin, NT‐pro‐BNP, cotinine, apolipoprotein A, and waist circumference (plus 10 more); in PAD they were age, high‐sensitivity C‐reactive protein, systolic blood pressure, expired carbon monoxide, cotinine, socioeconomic status, and lipoprotein (a) (plus 5 more). ConclusionsThe mixture of shared with disparate determinants for arterial disease in the heart and the legs implies nonidentical pathogenesis: cholesterol dominant in the former, and inflammation (high‐sensitivity C‐reactive protein, diabetes mellitus, smoking) in the latter.

Background: The burden of non-communicable diseases (NCDs) is increasing in low-to middleincomecountries (LMIC), increasing disproportionately for women in LMIC compared to women inhigh income countries. [...]

BackgroundEchogenicity is an ultrasound measure that reflects arterial wall composition. In adult populations, lower carotid intima‐media echogenicity relates to an unfavorable cardiovascular risk burden yet appears to reflect a different aspect of arterial wall remodeling than carotid intima‐media thickness (CIMT). Since studies on carotid intima‐media echogenicity earlier in life are lacking, we investigated associations between adolescent cardiovascular risk factors and young adulthood carotid intima‐media echogenicity and compared this to CIMT. Methods and ResultsIn 736 participants of the Atherosclerosis Risk in Young Adults study, information on adolescent anthropometrics, puberty stage, and systolic blood pressure (SBP) was available. In young adulthood, demographics, anthropometrics, and fasting plasma samples were collected. Common CIMT and echogenicity, quantified as gray‐scale median (GSM), were evaluated using B‐mode ultrasonography. Lower and higher GSM values, respectively, represented lower and higher echogenicity. Associations of adolescent body mass index and SBP with young adulthood GSM and CIMT were evaluated using linear regression analysis. Mean age was 13.5 years in adolescence and 28.4 years in young adulthood (difference: 14.9 years). After full adjustment, adolescent body mass index related to GSM (β=−1.62/SD; 95% CI: −2.79, −0.46; P=0.006), independent of CIMT. Adolescent SBP did not relate to GSM. Moreover, adolescent body mass index (β=8.06 μm/SD [95% CI: 4.12, 11.99], P

In Australia, manufacturers can use two government-endorsed approaches to advertise product healthiness: the Health Star Rating (HSR) front-of-pack nutrition labelling system, and health claims. Related, but different, algorithms determine the star rating of a product (the HSR algorithm) and eligibility to display claims (the Nutrient Profiling Scoring Criterion (NPSC) algorithm). The objective of this study was to examine the agreement between the HSR and NPSC algorithms. Food composition information for 41,297 packaged products was extracted from The George Institute’s FoodSwitch database. HSR and the NPSC scores were calculated, and the proportion of products in each HSR category that were eligible to display a health claim under the NPSC was examined. The highest agreement between the HSR scoring algorithm and the NPSC threshold to determine eligibility to display a health claim was at the HSR cut-off of 3.5 stars (k = 0.83). Overall, 97.3% (n = 40,167) of products with star ratings of 3.5 or higher were also eligible to display a health claim, and 94.3% (n = 38,939) of products with star ratings less than 3.5 were ineligible to display a health claim. The food group with greatest divergence was “edible oils”, with 45% products (n = 342) with HSR >3.5, but 64% (n = 495) eligible to display a claim. Categories with large absolute numbers of products with HSR

Background: The Health Star Rating (HSR) is an interpretive front-of-pack labelling system that rates the overall nutritional profile of packaged foods. The algorithm underpinning the HSR includes total sugar content as one of the components. This has been criticised because intrinsic sugars naturally present in dairy, fruits, and vegetables are treated the same as sugars added during food processing. We assessed whether the HSR could better discriminate between core and discretionary foods by including added sugar in the underlying algorithm. Methods: Nutrition information was extracted for 34,135 packaged foods available in The George Institute’s Australian FoodSwitch database. Added sugar levels were imputed from food composition databases. Products were classified as ‘core’ or ‘discretionary’ based on the Australian Dietary Guidelines. The ability of each of the nutrients included in the HSR algorithm, as well as added sugar, to discriminate between core and discretionary foods was estimated using the area under the curve (AUC). Results: 15,965 core and 18,350 discretionary foods were included. Of these, 8230 (52%) core foods and 15,947 (87%) discretionary foods contained added sugar. Median (Q1, Q3) HSRs were 4.0 (3.0, 4.5) for core foods and 2.0 (1.0, 3.0) for discretionary foods. Median added sugar contents (g/100 g) were 3.3 (1.5, 5.5) for core foods and 14.6 (1.8, 37.2) for discretionary foods. Of all the nutrients used in the current HSR algorithm, total sugar had the greatest individual capacity to discriminate between core and discretionary foods; AUC 0.692 (0.686; 0.697). Added sugar alone achieved an AUC of 0.777 (0.772; 0.782). A model with all nutrients in the current HSR algorithm had an AUC of 0.817 (0.812; 0.821), which increased to 0.871 (0.867; 0.874) with inclusion of added sugar. Conclusion: The HSR nutrients discriminate well between core and discretionary packaged foods. However, discrimination was improved when added sugar was also included. These data argue for inclusion of added sugar in an updated HSR algorithm and declaration of added sugar as part of mandatory nutrient declarations.

Objective To assess whether the risk of cardiovascular complications of covid-19 differ between the sexes and to determine whether any sex differences in risk are reduced in individuals with pre-existing cardiovascular disease.Design Registry based observational study.Setting 74 hospitals across 13 countries (eight European) participating in CAPACITY-COVID (Cardiac complicAtions in Patients With SARS Corona vIrus 2 regisTrY), from March 2020 to May 2021Participants All adults (aged ≥18 years), predominantly European, admitted to hospital with highly suspected covid-19 disease or covid-19 disease confirmed by positive laboratory test results (n=11 167 patients).Main outcome measures Any cardiovascular complication during admission to hospital. Secondary outcomes were in-hospital mortality and individual cardiovascular complications with ≥20 events for each sex. Logistic regression was used to examine sex differences in the risk of cardiovascular outcomes, overall and grouped by pre-existing cardiovascular disease.Results Of 11 167 adults (median age 68 years, 40% female participants) included, 3423 (36% of whom were female participants) had pre-existing cardiovascular disease. In both sexes, the most common cardiovascular complications were supraventricular tachycardias (4% of female participants, 6% of male participants), pulmonary embolism (3% and 5%), and heart failure (decompensated or de novo) (2% in both sexes). After adjusting for age, ethnic group, pre-existing cardiovascular disease, and risk factors for cardiovascular disease, female individuals were less likely than male individuals to have a cardiovascular complication (odds ratio 0.72, 95% confidence interval 0.64 to 0.80) or die (0.65, 0.59 to 0.72). Differences between the sexes were not modified by pre-existing cardiovascular disease; for the primary outcome, the female-to-male ratio of the odds ratio in those without, compared with those with, pre-existing cardiovascular disease was 0.84 (0.67 to 1.07).Conclusions In patients admitted to hospital for covid-19, female participants were less likely than male participants to have a cardiovascular complication. The differences between the sexes could not be attributed to the lower prevalence of pre-existing cardiovascular disease in female individuals. The reasons for this advantage in female individuals requires further research.

BackgroundWomen with peripheral artery disease (PAD) often have atypical symptoms, late hospital presentations, and worse prognosis. Risk factor identification and management are important. We assessed sex differences in associations of risk factors with PAD.Methods500,207 UK Biobank participants (54.5% women, mean age 56.5 years) without prior hospitalisation of PAD at baseline were included. Examined risk factors included blood pressure, smoking, diabetes, lipids, adiposity, history of stroke or myocardial infarction (MI), socioeconomic status, kidney function, C-reactive protein, and alcohol consumption. Poisson and Cox regressions were used to estimate sex-specific incidence of PAD hospitalisation or death, hazard ratios (HRs), and women-to-men ratios of HRs (RHR) with confidence intervals (CIs).ResultsOver a median of 12.6 years, 2658 women and 5002 men had a documented PAD. Age-adjusted incidence rates were higher in men. Most risk factors were associated with a higher risk of PAD in both sexes. Compared with men, women who were smokers or had a history of stroke or MI had a greater excess risk of PAD (relative to those who never smoked or had no history of stroke or MI): RHR 1.18 (95%CI 1.04, 1.34), 1.26 (1.02, 1.55), and 1.50 (1.25, 1.81), respectively. Higher high-density lipoprotein cholesterol (HDL-C) was more strongly associated with a lower risk of PAD in women than men, RHR 0.81 (0.68, 0.96). Compared to HDL-C at 40 to 60 mg/dL, the lowest level of HDL-C (≤40 mg/dL) was related to greater excess risk in women, RHR 1.20 (1.02, 1.41), whereas the highest level of HDL-C (>80 mg/dL) was associated with lower risk of PAD in women, but higher risk in men, RHR 0.50 (0.38, 0.65).ConclusionsWhile the incidence of PAD was higher in men, smoking and a history of stroke or MI were more strongly associated with a higher risk of PAD in women than men. HDL-C was more strongly associated with a lower risk of PAD in women than men.