A Global Perspective on Cardiovascular Risk Factors by Educational Level in CHD Patients: SURF CHD II.

Background: Clinical guidelines recommend lifestyle modifications and medication use to control cardiovascular risk factors in coronary heart disease (CHD) patients. However, risk factor control remains challenging especially in patients with lower educational level. Objective: To assess inequalities by educational level in the secondary prevention of CHD in the Survey of Risk Factors in Coronary Heart Disease (SURF CHD II). Methods: SURF CHD II is a cross-sectional clinical audit on secondary prevention of CHD, conducted during routine clinical visits in 29 countries. The easy-to-perform design of the survey facilitates its implementation in settings with limited resources. We reported risk factor recording, attainment of guideline-defined risk factor targets, and treatment in CHD patients. Differences by educational level in target attainment and treatment were assessed with logistic regression stratified for high- (HIC), upper middle- (UMIC), and lower middle-income (LMIC) countries. Results: SURF CHD II included 13,884 patients from 2019 to 2022, of which 25.0% were female and 18.6% had achieved only primary school level. Risk factor recording ranged from 22.2% for waist circumference to 95.6% for smoking status, and target attainment from 15.9% for waist circumference to 78.7% for smoking. Most patients used cardioprotective medications and 50.5% attended cardiac rehabilitation.Patients with secondary or tertiary education were more likely to meet targets for smoking, LDL cholesterol and physical activity in HICs and LMICs; for physical activity and triglycerides in UMICs; but less likely to meet targets for blood pressure in HICs and LDL <1.4mmol/L in UMICs. Higher education was positively associated with medication use and cardiac rehabilitation participation. Conclusion: CHD patients generally have poor attainment of risk factor targets, but patients with a higher educational level are generally more likely to participate in cardiac rehabilitation, use medication, and meet targets. Main messages: Target attainment and participation in cardiac rehabilitation are poor in CHD patients globally.Patients with higher education are more likely to meet risk factor targets, showing health inequities in secondary prevention of CHD.The association between education and risk factor target attainment and treatment varies with country income level.

Eligibility of Asian and European registry patients for phase III trials in heart failure with reduced ejection fraction.

AIMS: Traditional approaches to designing clinical trials for heart failure (HF) have historically relied on expertise and past practices. However, the evolving landscape of healthcare, marked by the advent of novel data science applications and increased data availability, offers a compelling opportunity to transition towards a data-driven paradigm in trial design. This research aims to evaluate the scope and determinants of disparities between clinical trials and registries by leveraging natural language processing for the analysis of trial eligibility criteria. The findings contribute to the establishment of a robust design framework for guiding future HF trials. METHODS AND RESULTS: Interventional phase III trials registered for HF on ClinicalTrials.gov as of the end of 2021 were identified. Natural language processing was used to extract and structure the eligibility criteria for quantitative analysis. The most common criteria for HF with reduced ejection fraction (HFrEF) were applied to estimate patient eligibility as a proportion of registry patients in the ASIAN-HF (N = 4868) and BIOSTAT-CHF registries (N = 2545). Of the 375 phase III trials for HF, 163 HFrEF trials were identified. In these trials, the most frequently encountered inclusion criteria were New York Heart Association (NYHA) functional class (69%), worsening HF (23%), and natriuretic peptides (18%), whereas the most frequent comorbidity-based exclusion criteria were acute coronary syndrome (64%), renal disease (55%), and valvular heart disease (47%). On average, 20% of registry patients were eligible for HFrEF trials. Eligibility distributions did not differ (P = 0.18) between Asian [median eligibility 0.20, interquartile range (IQR) 0.08-0.43] and European registry populations (median 0.17, IQR 0.06-0.39). With time, HFrEF trials became more restrictive, where patient eligibility declined from 0.40 in 1985-2005 to 0.19 in 2016-2022 (P = 0.03). When frequency among trials is taken into consideration, the eligibility criteria that were most restrictive were prior myocardial infarction, NYHA class, age, and prior HF hospitalization. CONCLUSIONS: Based on 14 trial criteria, only one-fifth of registry patients were eligible for phase III HFrEF trials. Overall eligibility rates did not differ between the Asian and European patient cohorts.

Longitudinal associations of air pollution and green space with cardiometabolic risk factor clustering among children in the Netherlands.

BACKGROUND: This study examines longitudinal associations of air pollution and green space with cardiometabolic risk among children in the Netherlands. METHODS: Three Dutch prospective cohorts with a total of 13,822 participants aged 5 to 17 years were included: (1) the Amsterdam Born Children and their Development (ABCD) study from Amsterdam (n = 2,547), (2) the Generation R study from Rotterdam (n = 5,431), and (3) the Lifelines study from northern Netherlands (n = 5,844). Air pollution (PM2.5, PM10, NO2, and elemental carbon (EC)) and green space exposures (density in multiple Euclidean buffer sizes) from 2006 to 2017 at home address level were used. Cardiometabolic risk factor clustering was assessed by a MetScore, which was derived from a confirmatory factor analysis of six cardiometabolic risk factors to assess the overall risk. Linear regression models with change in Metscore as the dependent variable, adjusted for multiple confounders, were conducted for each cohort separately. Meta-analyses were used to pool cohort-specific estimates. RESULTS: Exposure to higher levels of NO2 and EC was significantly associated with increases in MetScore in Lifelines (per SD higher exposure: ßNO2 = 0.006, 95 % CI = 0.001 to 0.010; ßEC = 0.008, 95 % CI = 0.002 to 0.014). In the other two cohort studies, these associations were in the same direction but these were not significant. Higher green space density in 500-meter buffer zones around participants' residential addresses was not significantly associated with decreases of MetScore in all three cohorts. Higher green space density in 2000-meter buffer zones was significantly associated with decreases of MetScore in ABCD and Lifelines (per SD higher green space density: ßABCD = -0.008, 95 % CI = -0.013 to -0.003; ßLifelines = -0.002, 95 % CI = -0.003 to -0.00003). The pooled estimates were ßNO2 = 0.003 (95 % CI = -0.001 to 0.006) for NO2, ßEC = 0.003 (95 % CI = -0.001, 0.007) for EC, and ß500m buffer = -0.0014 (95 % CI = -0.0026 to -0.0001) for green space. CONCLUSIONS: More green space exposure at residence was associated with decreased cardiometabolic risk in children. Exposure to more NO2 and EC was also associated with increased cardiometabolic risk.

Influenza Infection and Acute Myocardial Infarction.

BACKGROUND: Acute respiratory infections can trigger acute myocardial infarction. We aimed to quantify the association between laboratory-confirmed influenza infection and acute myocardial infarction, particularly in patients with and without known coronary artery disease. METHODS: This observational, registry-based, self-controlled case series study evaluated the association between laboratory-confirmed influenza infection and occurrence of acute myocardial infarction. Laboratory records on respiratory virus polymerase chain reaction (PCR) testing from 16 laboratories across the Netherlands were linked to national mortality, hospitalization, medication, and administrative registries. Influenza infection was defined as a positive PCR test result. Acute myocardial infarction was defined as a registered diagnostic code for either acute myocardial infarction hospitalization or death. Using a self-controlled case series method, we then compared the incidence of acute myocardial infarction during the risk period (days 1 to 7 after influenza infection) versus the control period (1 year before and 51 weeks after the risk period). RESULTS: Between 2008 and 2019, we identified 158,777 PCR tests for influenza in the study population; 26,221 were positive for influenza, constituting 23,405 unique influenza illness episodes. A total of 406 episodes were identified with acute myocardial infarction occurring within 1 year before and 1 year after confirmed influenza infection and were included in analysis. Twenty-five cases of acute myocardial infarction occurred during the risk period versus 394 during the control period. The adjusted relative incidence of acute myocardial infarction during the risk period compared with the control period was 6.16 (95% confidence interval [CI], 4.11 to 9.24). The relative incidence of acute myocardial infarction in individuals without prior hospitalization for coronary artery disease was 16.60 (95% CI, 10.45 to 26.37) compared with 1.43 (95% CI, 0.53 to 3.84) for those with prior admission for coronary artery disease. CONCLUSIONS: Influenza infection was associated with an increased risk of acute myocardial infarction, especially in individuals without a prior hospitalization for coronary artery disease. (Funded by the Dutch Research Council [NWO].).

Sex Differences in Mortality Risk after the First Hospitalisation with Lower Extremity Peripheral Arterial Disease.

OBJECTIVE: Lower extremity peripheral arterial disease (PAD) is a severe condition that increases the risk of major adverse cardiovascular events, major adverse limb events, and all cause mortality. This study aimed to investigate the mortality risk among females and males hospitalised for the first time with lower extremity PAD. METHODS: Three cohorts of patients who were admitted for the first time with lower extremity PAD in 2007 - 2010, 2011 - 2014, and 2015 - 2018 were constructed. For the 2007 - 2010 and 2011 - 2014 cohorts, the 28 day, one year, and five year mortality rates were calculated, assessing survival time from date of hospital admission until date of death, end of study period, or censoring. For the 2015 - 2018 cohort, only 28 day and one year mortality were investigated due to lack of follow up data. Mortality rates of these cohorts were compared with the general population using standardised mortality rates (SMRs), and the risk of death between sexes was evaluated using Cox proportional hazards models. Cox models were adjusted for age, cardiovascular disease, and diabetes mellitus to account for potential confounding factors. RESULTS: In total, 7 950, 9 670, and 13 522 patients were included in the 2007 - 2010, 2011 - 2014, and 2015 - 2018 cohorts, respectively. Over 60% of individuals in each cohort were males. Mortality rates at 28 day and one year remained stable across all cohorts, while the five year mortality rate increased for both males and females in the 2011 - 2014 cohort. The SMRs both of females and males with PAD were significantly higher than in the general population. Multivariable regression analyses found no significant differences in mortality risk between sexes at 28 day and one year. However, the five year mortality risk was lower in females, with a hazard ratio of 0.89 (95% confidence interval [CI] 0.83 - 0.97) in the 2007 - 2010 cohort and 0.88 (95% CI 0.82 - 0.94) in the 2011 - 2014 cohort. CONCLUSION: The five year mortality risk has increased, and females face a lower mortality risk than males. Lower extremity PAD still carries unfavourable long term consequences compared with the general population.

Dutch cardio-oncology cohort: Incident cardiovascular disease predisposes to a higher cancer mortality rate.

BACKGROUND: Cardiovascular disease (CVD) and cancer are the two leading causes of death worldwide. Given their high prevalence, it is important to understand the disease burden of cancer mortality in CVD patients. OBJECTIVE: We aimed to evaluate whether patients with incident CVD have a higher risk of malignancy-related mortality, compared to the general population without CVD. METHODS: We performed a national population-based cohort study selecting patients with incident CVD in the Netherlands between 01 April 2000 and 31 December 2005. A reference cohort was selected from the Dutch population using age, sex and ethnicity. Mortality follow-up data were evaluated after data linkage of national registries from Statistics Netherlands until 31 December 2020. RESULTS: A total of 2,240,879 individuals were selected with a mean follow-up of 12 years (range 0.4-21.0), of which 738,666 patients with incident CVD with a mean age of 71 ± 15 years. Malignancy mortality per 1000 person years was 84 for the reference group and 118 for patients with CVD, with the highest rate of 258 in patients with heart failure. Patients with CVD had a higher malignancy mortality risk, compared to the reference group: HR 1.35 (95%CI 1.33-1.36). Highest risks were observed in patients with venous diseases (HR 2.27, 95%CI 2.17-2.36) and peripheral artery disease (HR 1.87, 95%CI 1.84-2.01). CONCLUSION: Results show that CVD predisposes to a higher cancer mortality rate. Of all CVD subtypes, HF patients have the highest cancer mortality rate and the hazards were highest in patients with venous diseases and peripheral artery disease.

The association of obesogenic environments with weight status, blood pressure, and blood lipids: A cross-sectional pooled analysis across five cohorts.

In this observational cross-sectional study, we investigated the relationship between combined obesogenic neighbourhood characteristics and various cardiovascular disease risk factors in adults, including BMI, systolic blood pressure, and blood lipids, as well as the prevalence of overweight/obesity, hypertension, and dyslipidaemia. We conducted a large-scale pooled analysis, comprising data from five Dutch cohort studies (n = 183,871). Neighbourhood obesogenicity was defined according to the Obesogenic Built-environmental CharacterisTics (OBCT) index. The index was calculated for 1000m circular buffers around participants' home addresses. For each cohort, the association between the OBCT index and prevalence of overweight/obesity, hypertension and dyslipidaemia was analysed using robust Poisson regression models. Associations with continuous measures of BMI, systolic blood pressure, LDL-cholesterol, HDL-cholesterol, and triglycerides were analysed using linear regression. All models were adjusted for age, sex, education level and area-level socio-economic status. Cohort-specific estimates were pooled using random-effects meta-analyses. The pooled results show that a 10 point higher OBCT index score was significantly associated with a 0.17 higher BMI (95%CI: 0.10 to 0.24), a 0.01 higher LDL-cholesterol (95% CI: 0.01 to 0.02), a 0.01 lower HDL cholesterol (95% CI: -0.02 to -0.01), and non-significantly associated with a 0.36 mmHg higher systolic blood pressure (95%CI: -0.14 to 0.65). A 10 point higher OBCT index score was also associated with a higher prevalence of overweight/obesity (PR = 1.03; 95% CI: 1.02 to 1.05), obesity (PR = 1.04; 95% CI: 1.01 to 1.08) and hypertension (PR = 1.02; 95% CI: 1.00 to 1.04), but not with dyslipidaemia. This large-scale pooled analysis of five Dutch cohort studies shows that higher neighbourhood obesogenicity, as measured by the OBCT index, was associated with higher BMI, higher prevalence of overweight/obesity, obesity, and hypertension. These findings highlight the importance of considering the obesogenic environment as a potential determinant of cardiovascular health.

Impact of green space exposure on blood pressure in Guangzhou, China: Mediation by air pollution, mental health, physical activity, and weight status.

Green space exposure has been inversely associated with blood pressure (BP) levels and hypertension risk. However, empirical evidence on the underlying mechanisms are lacking. This study examined the association of green space exposure with BP and hypertension, and assessed the mediating effects by air pollution, mental health, physical activity, and weight status. Survey data from 719 adults, who lived in Guangzhou (China) in 2016, were used. Three area-level green space indicators, including network distance to the nearest park, percentage of green space and Normalized Difference Vegetation Index within a 1 km Euclidean buffer around residence and workplace, were calculated and linked to individual-level BP measurements. Structural equation models were applied to estimate the direct and indirect associations of the various green space indicators on systolic BP (SBP), diastolic BP (DBP), and hypertension, respectively. After adjusting for multiple covariates, longer network distance to green space was directly associated with higher SBP. Compared to the reference group (0-500m), the differences were 0.11 mmHg (95% CI = 0.03 to 0.19, P = 0.006) for 500-1000m, 0.03 mmHg (95% CI = -0.05 to 0.12, P = 0.45) for 1000-1500m, and 0.16 mmHg (95% CI = 0.09 to 0.23, P < 0.001) for >1500m, respectively. The overall and direct associations were significant for all three indicators (distance or density) with or without considering workplace exposure. The association between network distance to green and SBP was partially (18.4%, 95% CI = 0-42.1%) mediated by mental health. There was no statistical evidence that air pollution, physical activity, or weight status mediate the association. Secondary analyses for other indicators and other outcomes showed similar results. Both distance to green space and more green space around residence and workplace were associated with lower BP and lower risk of hypertension in adults living in a Chinese metropolitan. Mental health partly mediated the association.

The neighourhood obesogenic built environment characteristics (OBCT) index: Practice versus theory.

BACKGROUND: Obesity is a key risk factor for major chronic diseases such as type 2 diabetes and cardiovascular diseases. To extensively characterise the obesogenic built environment, we recently developed a novel Obesogenic Built environment CharacterisTics (OBCT) index, consisting of 17 components that capture both food and physical activity (PA) environments. OBJECTIVES: We aimed to assess the association between the OBCT index and body mass index (BMI) in a nationwide health monitor. Furthermore, we explored possible ways to improve the index using unsupervised and supervised methods. METHODS: The OBCT index was constructed for 12,821 Dutch administrative neighbourhoods and linked to residential addresses of eligible adult participants in the 2016 Public Health Monitor. We split the data randomly into a training (two-thirds; n = 255,187) and a testing subset (one-third; n = 127,428). In the training set, we used non-parametric restricted cubic regression spline to assess index's association with BMI, adjusted for individual demographic characteristics. Effect modification by age, sex, socioeconomic status (SES) and urbanicity was examined. As improvement, we (1) adjusted the food environment for address density, (2) added housing price to the index and (3) adopted three weighting strategies, two methods were supervised by BMI (variable selection and random forest) in the training set. We compared these methods in the testing set by examining their model fit with BMI as outcome. RESULTS: The OBCT index had a significant non-linear association with BMI in a fully-adjusted model (p<0.05), which was modified by age, sex, SES and urbanicity. However, variance in BMI explained by the index was low (<0.05%). Supervised methods increased this explained variance more than non-supervised methods, though overall improvements were limited as highest explained variance remained <0.5%. DISCUSSION: The index, despite its potential to highlight disparity in obesogenic environments, had limited association with BMI. Complex improvements are not necessarily beneficial, and the components should be re-operationalised.

Ethnic and socioeconomic inequalities in air pollution exposure: a cross-sectional analysis of nationwide individual-level data from the Netherlands.

BACKGROUND: Air pollution contributes to a large disease burden and some populations are disproportionately exposed. We aimed to evaluate ethnic and socioeconomic differences in exposure to air pollution in the Netherlands. METHODS: We did a nationwide, cross-sectional analysis of all residents of the Netherlands on Jan 1, 2019. Sociodemographic information was centralised by Statistics Netherlands and mainly originated from the National Population Register, the tax register, and education registers. Concentrations of NO2, PM2·5, PM10, and elemental carbon, modelled by the National Institute for Public Health and the Environment, were linked to the individual-level demographic data. We assessed differences in air pollution exposures across the 40 largest minority ethnic groups. Evaluation of how ethnicity intersected with socioeconomic position in relation to exposures was done for the ten largest ethnic groups, plus Chinese and Indian groups, in both urban and rural areas using multivariable linear regression analyses. FINDINGS: The total study population consisted of 17 251 511 individuals. Minority ethnic groups were consistently exposed to higher levels of air pollution than the ethnic Dutch population. The magnitude of inequalities varied between the minority ethnic groups, with 3-44% higher exposures to NO2 and 1-9% higher exposures to PM2·5 compared with the ethnic Dutch group. Average exposures were highest for the lowest socioeconomic group. Ethnic inequalities in exposure remained after adjustment for socioeconomic position and were of similar magnitude in urban and rural areas. INTERPRETATION: The variability in air pollution exposure across ethnic and socioeconomic subgroups in the Netherlands indicates environmental injustice at the intersection of social characteristics. The health consequences of the observed inequalities and the underlying processes driving them warrant further investigation. FUNDING: The Gravitation programme of the Dutch Ministry of Education, Culture, and Science, the Netherlands Organization for Scientific Research, the Netherlands Organisation for Health Research and Development, and Amsterdam University Medical Center.

Does Heterogeneity Exist in Treatment Associations With Renin-Angiotensin-System Inhibitors or Beta-blockers According to Phenotype Clusters in Heart Failure with Preserved Ejection Fraction?

BACKGROUND: We explored the association between use of renin-angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young-low comorbidity burden (12%), atrial fibrillation-hypertensive (32%), older-atrial fibrillation (24%), obese-diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin-angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young-low comorbidity burden and atrial fibrillation-hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese-diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar. CONCLUSIONS: In patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design.

Towards Better Culturally Tailored Cardiometabolic Prevention Among the South-Asian Surinamese in the Netherlands.

Objectives: To gain insight in the motives and determinants for the uptake of healthy lifestyles by South-Asian Surinamese people to identify needs and engagement strategies for healthy lifestyle support. Methods: We used a mixed-method design: first, focus groups with South-Asian Surinamese women; second, a questionnaire directed at their social network, and third, interviews with health professionals. Qualitative content analysis, basic statistical analyses and triangulation of data were applied. Results: Sixty people participated (n = 30 women, n = 20 social network, n = 10 professionals). Respondent groups reported similar motives and determinants for healthy lifestyles. In general, cardiometabolic prevention was in line with the perspectives and needs of South-Asian Surinamese. However, there seems to be a mismatch too: South-Asian Surinamese people missed a culturally sensitive approach, whereas professionals experienced difficulty with patient adherence. Incremental changes to current lifestyles; including the social network, and an encouraging approach seem to be key points for improvement of professional cardiometabolic prevention. Conclusion: Some key points for better culturally tailoring of preventive interventions would meet the needs and preferences of the South-Asian Surinamese living in the Netherlands.

Risk factors in cardiovascular patients: Challenges and opportunities to improve secondary prevention.

BACKGROUND: Effective management of major cardiovascular risk factors is of great importance to reduce mortality from cardiovascular disease (CVD). The Survey of Risk Factors in Coronary Heart Disease (SURF CHD) II study is a clinical audit of the recording and management of CHD risk factors. It was developed in collaboration with the European Association of Preventive Cardiology and the European Society of Cardiology (ESC). Previous studies have shown that control of major cardiovascular risk factors in patients with established atherosclerotic CVD is generally inadequate. Azerbaijan is a country in the South Caucasus, a region at a very high risk for CVD. AIM: To assess adherence to ESC recommendations for secondary prevention of CVD based on the measurement of both modifiable major risk factors and their therapeutic management in patients with confirmed CHD at different hospitals in Baku (Azerbaijan). METHODS: Six tertiary health care centers participated in the SURF CHD II study between 2019 and 2021. Information on demographics, risk factors, physical and laboratory data, and medications was collected using a standard questionnaire in consecutive patients aged ≥ 18 years with established CHD during outpatient visits. Data from 687 patients (mean age 59.6 ± 9.58 years; 24.9% female) were included in the study. RESULTS: Only 15.1% of participants were involved in cardiac rehabilitation programs. The rate of uncontrolled risk factors was high: Systolic blood pressure (BP) (SBP) (54.6%), low-density lipoprotein cholesterol (LDL-C) (86.8%), diabetes mellitus (DM) (60.6%), as well as overweight (66.6%) and obesity (25%). In addition, significant differences in the prevalence and control of some risk factors [smoking, body mass index (BMI), waist circumference, blood glucose (BG), and SBP] between female and male participants were found. The cardiovascular health index score (CHIS) was calculated from the six risk factors: Non- or ex-smoker, BMI < 25 kg/m2, moderate/vigorous physical activity, controlled BP (< 140/90 mmHg; 140/80 mmHg for patients with DM), controlled LDL-C (< 70 mg/dL), and controlled BG (glycohemoglobin < 7% or BG < 126 mg/dL). Good, intermediate, and poor categories of CHIS were identified in 6%, 58.3%, and 35.7% of patients, respectively (without statistical differences between female and male patients). CONCLUSION: Implementation of the current ESC recommendations for CHD secondary prevention and, in particular, the control rate of BP, are insufficient. Given the fact that patients with different comorbid pathologies are at a very high risk, this is of great importance in the management of such patients. This should be taken into account by healthcare organizers when planning secondary prevention activities and public health protection measures, especially in the regions at a high risk for CVD. A wide range of educational products based on the Clinical Practice Guidelines should be used to improve the adherence of healthcare professionals and patients to the management of CVD risk factors.

Discovering Distinct Phenotypical Clusters in Heart Failure Across the Ejection Fraction Spectrum: a Systematic Review.

REVIEW PURPOSE: This systematic review aims to summarise clustering studies in heart failure (HF) and guide future clinical trial design and implementation in routine clinical practice. FINDINGS: 34 studies were identified (n = 19 in HF with preserved ejection fraction (HFpEF)). There was significant heterogeneity invariables and techniques used. However, 149/165 described clusters could be assigned to one of nine phenotypes: 1) young, low comorbidity burden; 2) metabolic; 3) cardio-renal; 4) atrial fibrillation (AF); 5) elderly female AF; 6) hypertensive-comorbidity; 7) ischaemic-male; 8) valvular disease; and 9) devices. There was room for improvement on important methodological topics for all clustering studies such as external validation and transparency of the modelling process. The large overlap between the phenotypes of the clustering studies shows that clustering is a robust approach for discovering clinically distinct phenotypes. However, future studies should invest in a phenotype model that can be implemented in routine clinical practice and future clinical trial design. HF = heart failure, EF = ejection fraction, HFpEF = heart failure with preserved ejection fraction, HFrEF = heart failure with reduced ejection fraction, CKD = chronic kidney disease, AF = atrial fibrillation, IHD = ischaemic heart disease, CAD = coronary artery disease, ICD = implantable cardioverter-defibrillator, CRT = cardiac resynchronization therapy, NT-proBNP = N-terminal pro b-type natriuretic peptide, BMI = Body Mass Index, COPD = Chronic obstructive pulmonary disease.

The built environment and cardiovascular disease: an umbrella review and meta-meta-analysis.

AIMS: To provide a comprehensive overview of the current evidence on objectively measured neighbourhood built environment exposures in relation to cardiovascular disease (CVD) events in adults. METHODS AND RESULTS: We searched seven databases for systematic reviews on associations between objectively measured long-term built environmental exposures, covering at least one domain (i.e. outdoor air pollution, food environment, physical activity environment like greenspace and walkability, urbanization, light pollution, residential noise, and ambient temperature), and CVD events in adults. Two authors extracted summary data and assessed the risk of bias independently. Robustness of evidence was rated based on statistical heterogeneity, small-study effect, and excess significance bias. Meta-meta-analyses were conducted to combine the meta-analysis results from reviews with comparable exposure and outcome within each domain. From the 3304 initial hits, 51 systematic reviews were included, covering 5 domains and including 179 pooled estimates. There was strong evidence of the associations between increased air pollutants (especially PM2.5 exposure) and increased residential noise with greater risk of CVD. Highly suggestive evidence was found for an association between increased ambient temperature and greater risk of CVD. Systematic reviews on physical activity environment, food environment, light pollution, and urbanization in relation to CVD were scarce or lacking. CONCLUSION: Air pollutants, increased noise levels, temperature, and greenspace were associated with CVD outcomes. Standardizing design and exposure assessments may foster the synthesis of evidence. Other crucial research gaps concern the lack of prospective study designs and lack of evidence from low-to-middle-income countries (LMICs). REGISTRATION: PROSPERO: CRD42021246580.

This study is a review of published systematic reviews on the relation between the neighbourhood built environment and cardiovascular disease (CVD) in adults. There was strong evidence of a relation between increased air pollutants and a greater risk of CVD. There was also strong evidence of a relation between increased residential noise and a greater risk of CVD. There was highly suggestive evidence of a relation between increased ambient temperature and a greater risk of CVD. Systematic reviews that examined other aspects of the built environment, such as the physical activity environment, food environment, light pollution, and urbanization, were scarce or lacking.

Identifying distinct clinical clusters in heart failure with mildly reduced ejection fraction.

INTRODUCTION: Heart failure (HF) is a heterogeneous syndrome, and the specific sub-category HF with mildly reduced ejection fraction (EF) range (HFmrEF; 41-49% EF) is only recently recognised as a distinct entity. Cluster analysis can characterise heterogeneous patient populations and could serve as a stratification tool in clinical trials and for prognostication. The aim of this study was to identify clusters in HFmrEF and compare cluster prognosis. METHODS AND RESULTS: Latent class analysis to cluster HFmrEF patients based on their characteristics was performed in the Swedish HF registry (n = 7316). Identified clusters were validated in a Dutch cross-sectional HF registry-based dataset CHECK-HF (n = 1536). In Sweden, mortality and hospitalisation across the clusters were compared using a Cox proportional hazard model, with a Fine-Gray sub-distribution for competing risks and adjustment for age and sex. Six clusters were discovered with the following prevalence and hazard ratio with 95% confidence intervals (HR [95%CI]) vs. cluster 1: 1) low-comorbidity (17%, reference), 2) ischaemic-male (13%, HR 0.9 [95% CI 0.7-1.1]), 3) atrial fibrillation (20%, HR 1.5 [95% CI 1.2-1.9]), 4) device/wide QRS (9%, HR 2.7 [95% CI 2.2-3.4]), 5) metabolic (19%, HR 3.1 [95% CI 2.5-3.7]) and 6) cardio-renal phenotype (22%, HR 2.8 [95% CI 2.2-3.6]). The cluster model was robust between both datasets. CONCLUSION: We found robust clusters with potential clinical meaning and differences in mortality and hospitalisation. Our clustering model could be valuable as a clinical differentiation support and prognostic tool in clinical trial design.

Sex differences in the generalizability of randomized clinical trials in heart failure with reduced ejection fraction.

AIMS: In order to understand how sex differences impact the generalizability of randomized clinical trials (RCTs) in patients with heart failure (HF) and reduced ejection fraction (HFrEF), we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex. METHODS AND RESULTS: Data from two HF registries and five HFrEF RCTs were used to create three subpopulations: one RCT population (n = 16 917; 21.7% females), registry patients eligible for RCT inclusion (n = 26 104; 31.8% females), and registry patients ineligible for RCT inclusion (n = 20 810; 30.2% females). Clinical endpoints included all-cause mortality, cardiovascular mortality, and first HF hospitalization at 1 year. Males and females were equally eligible for trial enrolment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups, respectively. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (standardized mortality ratio [SMR] 0.72; 95% confidence interval [CI] 0.62-0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09-1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95% CI 0.76-1.03 for females, SMR 1.43; 95% CI 1.33-1.53 for males). CONCLUSION: Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and female trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries.

Risk factor clustering in men and women with CHD in the Southern Cone of Latin America.

Background: Presence of multiple risk factors (RF) increases the risk for cardiovascular morbidity and mortality, and this is especially important in patients with coronary heart disease (CHD). The current study investigates sex differences in the presence of multiple cardiovascular RF in subjects with established CHD in the southern Cone of Latin America. Methods: We analyzed cross-sectional data from the 634 participants aged 35-74 with CHD from the community-based CESCAS Study. We calculated the prevalence for counts of cardiometabolic (hypertension, dyslipidemia, obesity, diabetes) and lifestyle (current smoking, unhealthy diet, low physical activity, excessive alcohol consumption) RF. Differences in RF number between men and women were tested with age-adjusted Poisson regression. We identified the most common RF combinations among participants with ≥4 RF. We performed a subgroup analysis by educational level. Results: The prevalence of cardiometabolic RF ranged from 76.3% (hypertension) to 26.8% (diabetes), and the prevalence of lifestyle RF from 81.9% (unhealthy diet) to 4.3% (excessive alcohol consumption). Obesity, central obesity, diabetes and low physical activity were more common in women, while excessive alcohol consumption and unhealthy diet were more common in men. Close to 85% of women and 81.5% of men presented with ≥4 RF. Women presented with a higher number of overall (relative risk (RR) 1.05, 95% CI 1.02-1.08) and cardiometabolic RF (1.17, 1.09-1.25). These sex differences were found in participants with primary education (RR women overall RF 1.08, 1.00-1.15, cardiometabolic RF 1.23, 1.09-1.39), but were diluted in those with higher educational attainment. The most common RF combination was hypertension/dyslipidemia/obesity/unhealthy diet. Conclusion: Overall, women showed a higher burden of multiple cardiovascular RF. Sex differences persisted in participants with low educational attainment, and women with low educational level had the highest RF burden.

Association of Stroke at Young Age With New Cancer in the Years After Stroke Among Patients in the Netherlands.

Importance: Stroke may be a first manifestation of an occult cancer or may be an indicator of an increased cancer risk in later life. However, data, especially for younger adults, are limited. Objectives: To assess the association of stroke with new cancer diagnoses after a first stroke, stratified by stroke subtype, age, and sex, and to compare this association with that in the general population. Design, Setting, and Participants: This registry- and population-based study included 390 398 patients in the Netherlands aged 15 years or older without a history of cancer and with a first-ever ischemic stroke or intracerebral hemorrhage (ICH) between January 1, 1998, and January 1, 2019. Patients and outcomes were identified through linkage of the Dutch Population Register, the Dutch National Hospital Discharge Register, and National Cause of Death Register. Reference data were gathered from the Dutch Cancer Registry. Statistical analysis was performed from January 6, 2021, to January 2, 2022. Exposure: First-ever ischemic stroke or ICH. Patients were identified by administrative codes from the International Classification of Diseases, Ninth Revision, and the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. Main Outcomes and Measures: The primary outcome was the cumulative incidence of first-ever cancer after index stroke, stratified by stroke subtype, age, and sex, compared with age-, sex- and calendar year-matched peers from the general population. Results: The study included 27 616 patients aged 15 to 49 years (median age, 44.5 years [IQR, 39.1-47.6 years]; 13 916 women [50.4%]; 22 622 [81.9%] with ischemic stroke) and 362 782 patients aged 50 years or older (median age, 75.8 years [IQR, 66.9-82.9 years]; 181 847 women [50.1%]; 307 739 [84.8%] with ischemic stroke). The cumulative incidence of new cancer at 10 years was 3.7% (95% CI, 3.4%-4.0%) among patients aged 15 to 49 years and 8.5% (95% CI, 8.4%-8.6%) among patients aged 50 years or older. The cumulative incidence of new cancer after any stroke among patients aged 15 to 49 years was higher among women than men (Gray test statistic, 22.2; P < .001), whereas among those aged 50 years or older, the cumulative incidence of new cancer after any stroke was higher among men (Gray test statistic, 943.1; P < .001). In the first year after stroke, compared with peers from the general population, patients aged 15 to 49 years were more likely to receive a diagnosis of a new cancer after ischemic stroke (standardized incidence ratio [SIR], 2.6 [95% CI, 2.2-3.1]) and ICH (SIR, 5.4 [95% CI, 3.8-7.3]). For patients aged 50 years or older, the SIR was 1.2 (95% CI, 1.2-1.2) after ischemic stroke and 1.2 (95% CI, 1.1-1.2) after ICH. Conclusions and Relevance: This study suggests that, compared with the general population, patients aged 15 to 49 years who have had a stroke may have a 3- to 5-fold increased risk of cancer in the first year after stroke, whereas this risk is only slightly elevated for patients aged 50 years or older. Whether this finding has implications for screening remains to be investigated.

Neighbourhood walkability in relation to cognitive functioning in patients with disorders along the heart-brain axis.

This study examined associations of neighbourhood walkability with cognitive functioning (i.e., global cognition, memory, language, attention-psychomotor speed, and executive functioning) in participants without or with either heart failure, carotid occlusive disease, or vascular cognitive impairment. Neighbourhood walkability at baseline was positively associated with global cognition and attention-psychomotor speed. These associations were stronger in patients with vascular cognitive impairment. Individuals who live in residential areas with higher walkability levels were less likely to have impairments in language and executive functioning at two-year follow-up. These findings highlight the importance of the built environment for cognitive functioning in healthy and vulnerable groups.