Elevated Risk Research Articles

Long-Term Impact of Infertility and Assisted Reproductive Technology on Cardio-Renal Health in Sweden

Abstract Background The use of Assisted Reproductive Technology (ART), such as in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI), is rising in Europe. These treatments involve high doses of hormones to increase oocyte collection. While most safety studies in women have focused on cancer risks, the association with cardio-renal diseases remains under-explored. This study examines whether the use of ART is linked to coronary ischemic disease (CHD), stroke, brain hemorrhage, other cerebrovascular diseases, chronic kidney disease, and aortic aneurysm/dissection, while also exploring the association between infertility and these conditions. Methods A nationwide cohort study was conducted using Swedish national registries, following all nulliparous women who gave birth between 1982 and 2002 until the end of 2017. Descriptive statistics and inverse probability weighted Kaplan-Meier curves to adjust for body mass index, maternal age, country of origin, smoking, and year of delivery, were used to compare 1) women who conceived with or without ART, 2) women who used IVF or ICSI respectively to women with known infertility that conceived without ART, and 3) women with and without known infertility. Results Compared to all other women, women undergoing ART were at elevated risk for CHD, stroke, and other cerebrovascular diseases, but after adjustment for underlying risk factors, including infertility, no substantial differences were seen. As a group, women with known infertility were at elevated risk of CHD and stroke, also after adjustment for known background factors. Conclusions Data suggest that the use of ART does not increase the long-term risk of cardio-renal diseases. Nonetheless, infertility itself is associated with a higher risk of CHD and stroke. Key messages • Infertility, more so than the use of ART, is linked to elevated risks of CHD and stroke. • Preventive measures for these conditions should be considered for women with infertility.

Relationship between renin, aldosterone, aldosterone-to-renin ratio and left ventricular mass index in young adults

Abstract Background Primary aldosteronism (PA), characterised by excessive aldosterone production and mineralocorticoid receptor activation, is associated with adverse cardiovascular outcomes including left ventricular hypertrophy and failure. Elevated cardiovascular risk is observed even in milder and subclinical forms of PA, especially in middle-aged and elderly populations. It is unclear if early changes in PA biomarkers can affect left ventricular mass index (LVMI), which is a strong predictor of cardiovascular diseases. Aim To evaluate the relationship between PA biomarkers, namely renin concentration, aldosterone concentration and aldosterone-to-renin ratio (ARR), and LVMI in young adults. Methods The Raine Study is a longitudinal, population-based cohort study in Western Australia that enrolled women during pregnancy. We analysed the data from the offspring of these women at age 27. Participants with PA biomarkers and LVMI measured by cardiac magnetic resonance imaging were included. Females who were on oral contraception were excluded due to its confounding effect on the ARR. We examined the relationship between LVMI and plasma renin, aldosterone, and ARR using multivariate-adjusted linear regression and used mediation analysis to test whether these relationships were dependent on systolic blood pressure (SBP). Results Of 758 participants, 252 (33.2%) were females and the mean (SD) age was 26.7 (0.4) years. Females had lower median plasma renin concentration (12.0 vs 15.4mU/L; p<0.001) and higher median ARR (21.0 vs 15.6; p<0.001) than males. There was no sex-difference in median plasma aldosterone concentration (257 vs 237pmol/L in males; p=0.143). Females had lower LVMI (52.2 vs 70.2 g/m²; p<0.001) than males. A significant association between LVMI and aldosterone was detected in males (β-coefficient 0.009; 95% CI 0.001 to 0.017; p=0.027), and between LVMI and ARR in females (β-coefficient 0.098; 95% CI 0.001 to 0.196; p=0.050) after adjusting for confounders. This relationship was not mediated by brachial SBP. Conclusion An elevated aldosterone concentration or ARR was associated with higher LVMI in young adults, independent of brachial SBP. Long-term follow-up is required to determine if the relationship persists over time and leads to reduced cardiac function. One may speculate that an intervention trial in young adults with subclinical PA is warranted to determine the role of aldosterone blockade in preventing future cardiovascular diseases.

Sex related cardiovascular risk is non-dichotomous: artificial intelligence enhanced electrocardiography reveals continuum of risk in females

Abstract Background Females are typically underserved in cardiovascular medicine and often considered lower risk of cardiovascular disease. The use of sex as a dichotomous variable for risk stratification fails to capture the heterogeneity of risk within each sex. Purpose We aimed to develop an artificial intelligence-enhanced ECG (AI-ECG)-derived continuous sex score that can capture the continuum of risk and sex phenotypes within each sex, with the particular goal of addressing the female disadvantage. Methods We trained a convolution neural network to identify sex using the 12-lead ECG. The derivation cohort was 1,163,401 ECGs from 189,538 subjects from a USA secondary care hospital cohort and validated inthe UK Biobank (UKB). The model outputs a continuous value from 0 to 1 for sex prediction. The AI-ECG sex discordance score is the difference between predicted sex and biological sex. Results AI-ECG accurately identified sex in both the USA cohort (AUROC 0.943 (0.942-0.943)) and UKB datasets (n = 42,386, AUROC 0.971 (0.969-0.972)). In explainability analyses we found QRS duration, T wave morphology, QT interval, heart rate and QRS voltage as the most important factors in contributing to AI-ECG sex identification. In females only but not in males, sex discordance score was associated with a covariate-adjusted increased risk of cardiovascular death in outpatients with normal ECGs from the USA cohort, (Females hazard ratio (HR) 1.64 (1.18-2.29) p = 0.003, Males HR 1.04 (0.66-1.63), p = 0.86). This pattern persisted in the UKB: Females HR 1.39 (1.08-1.78) p = 0.01, Males HR 0.97 (0.77-1.22), p = 0.80, Fig 1). In phenome-wide association studies, we found females with a higher sex score discordance were more likely to have heart failure or myocardial infarction. Covariate-adjusted cox models confirmed the association of sex score discordance with increased future heart failure (HR 1.21 (1.07-1.37) p = 0.002 and future myocardial infarction (HR 1.32 (1.11-1.56) p = 0.001). In age- and body size-adjusted analyses, females with higher sex discordance score had increased left ventricular mass, and chamber volumes as well as increased muscle mass, reduced body fat percentage (Fig 2). In a genome-wide association study of sex discordance score we identified variants adjacent to IGF1R and NDRG4 in females, which have been previously associated with LV mass and sex hormone levels (Fig 2). Conclusion We describe sex discordance score as a novel AI-ECG biomarker capable of identifying females with disproportionately elevated cardiovascular risk. Sex discordance score may help uncover potential underlying mechanisms of cardiovascular disease among females, and future clinical studies are needed to determine its potential utility in identification of females at higher risk of cardiovascular events. Rather than exacerbating biases, AI-ECG has the potential to reduce female cardiovascular health inequalities.

Combined mammographic breast density and breast arterial calcification is incrementally predictive of coronary artery disease beyond traditional risk factors

Abstract Background Coronary artery disease (CAD) risk is underestimated in women using current risk stratification tools. The mammographic finding of breast arterial calcification (BAC) associates with CAD. Furthermore, breast adipose tissue, measured through breast density (BD) on mammography (low breast density indicates high adiposity) has shown potential to act as a pro-inflammatory, pro-atherogenic fat deposit. Given its uptake in screening programs, mammography may therefore represent a novel risk stratification tool for cardiovascular disease in women. Purpose To evaluate the association between the combined mammographic features of BD and BAC, with CAD. Methods Single-centre, retrospective, cross-sectional study, including 153 women, mean age 62±10, who had both clinically indicated mammography, and coronary computed tomography angiogram (CCTA) for suspected CAD. CAD risk was identified by the CAD Consortium Score, with a 15% threshold for low and high risk. BD was visually assessed and categorised by 4-level BI-RADS grade with grade A-B representing low density, and C-D representing high density (Figure 1). BAC was visually assessed and categorised as present/absent (Figure 1). CAD was categorised as presence/absence of coronary artery plaque on CCTA. Logistic regression was performed with results presented as Odds Ratio (OR) and [95% Confidence Intervals]. Receiver operator characteristic area under the curve (AUC) was used for model discrimination. Results Low BD (n=103 (67%)) was associated with CAD (OR 3.20 [1.58-6.53], p=0.001, as was BAC presence (n=37 (24%), OR 4.36 [1.58-12], p=0.004). There were 51 (33%) with elevated CAD risk. Participants were categorised into 4 subgroups based on low/high BD and presence/absence of BAC: 29 (19%) had low BD and BAC, 74 (48%) had low BD and no BAC, 8 (5%) had high BD and BAC and 42 (27%) had high BD and no BAC. Significantly higher proportions of CAD were noted with low BD and BAC alone, as well as combined low BD and BAC (Figure 2). Compared with high BD/BAC negative, the presence of low BD and BAC independently associated with CAD (OR 5.27 [1.19-23.3], p=0.03). Significant incremental benefit was seen after adding BD/BAC status to CAD Consortium Score (AUC 0.65 vs. 0.72, p=0.004). Conclusions Combined, and individual mammographic features of low BD and BAC presence are associated with CAD and improve risk prediction beyond standard coronary risk probabilities. Standardised reporting of these features to inform risk identification may be of further benefit and should be tested in prospective screening studies.

Cardiovascular disease risk in people with diabetes in the era of universal diabetes screening

Abstract Background/Introduction Traditionally, most people with diabetes have been considered at high cardiovascular disease (CVD) risk and CVD preventive treatment has been recommended for almost all patients after diagnosis. However, guidelines are increasingly recommending a more stratified approach to preventive treatment informed by predicted CVD risk. In the early 2000’s, New Zealand initiated the world-first national diabetes screening programme, as a component of a national CVD risk assessment programme, and by 2016, approximately 90% of eligible New Zealand adults had been screened. We hypothesised that in the era of universal diabetes screening, many recently diagnosed patients will be at low CVD risk and that contemporary CVD risk prediction equations would be required to accurately assess their risk. Purpose We aimed to develop sex-specific 5-year CVD risk prediction models in people with diabetes in New Zealand using a contemporary natural-population based cohort, and to characterise the distribution of CVD risk. Methods De-identified individual-level linkage of multiple health administrative datasets was undertaken to establish a cohort of almost all adults with diabetes in the northern region of New Zealand (one-third of the national population), without CVD or heart failure, and aged 30–74 years on January 1, 2014, with follow-up linkage to hospitalisations and mortality until December 31, 2018. Sex-specific models were developed to estimate the 5-year risk of CVD hospitalisation or death, with 15 pre-defined predictors, including sociodemographic variables, diabetes-related and renal function measures. Results 64,645 participants (median age: 57 years [IQR: 49–65]) were included in the final cohort, of whom 4,992 had first CVD events during 301,272 person-years follow-up. Models calibrated well in both women and men (Figure 1). Overall, increasing age; high deprivation level; smoking-related hospitalisations or use of smoking cessation medications; history of atrial fibrillation; high levels of haemoglobin A1c, total cholesterol to HDL cholesterol ratio, and albumin-to-creatinine ratio; use of blood pressure-lowering medications and insulin were associated with elevated CVD risk. Median 5-year CVD risks were 4.9% (IQR: 2.9%–8.1%) in women and 7.7% (4.8%–12.0%) in men. There was a wide range of predicted 5-year CVD risk, with 51% of women and 27% of men having a predicted risk below 5%, and 6% of women and 16% of men having a risk of 15% or above (Figure 2). Conclusions This study demonstrated marked heterogeneity in predicted CVD risk in people with diabetes in an era of universal diabetes screening. As diabetes screening is increasingly undertaken as part of a routine CVD risk assessment, these findings will have important clinical implications for accurately targeting new but expensive CVD preventive medications to the highest risk patients.

Type 2 diabetes risk is associated with poorer general health and mental health in women and men

Abstract Background Increasing evidence points to a relation between cardiometabolic and mental health, but population-based data are scarce. We investigated the association of type 2 diabetes (T2D) risk to general and mental health with a focus on potential differences between women and men. Methods The study population comprised 5,192 adults (18+ years) without known diabetes based on data of the German Health Update (GEDA) 2022. T2D risk was assessed by the German Diabetes Risk Score (GDRS), that estimates the 5-year probability of developing T2D and was categorized into low, still low, elevated, and high risk. Sex-specific Poisson regression analyses were conducted including self-rated health (SRH), self-rated mental health (SRMH), depressive symptoms (PHQ-2) and anxiety symptoms (GAD-2) as dichotomous dependent variables and age, educational level, living alone, region of residence, and social support as covariables. Results Women had a higher prevalence of low T2D risk (66.1%) and a lower prevalence of high T2D risk (9.4 %) than men (55.3% vs. 16.3%). Compared to those with low T2D risk, women and men with a high T2D risk were less likely to report very good/good SRH (women: prevalence ratio: 0.63; 95% confidence interval: 0.51-0.79; men: 0.69; 0.57-0.84) or excellent/very good SRMH (women: 0.53, 0.39-0.73; men: 0.85, 0.63-1.15). Further, those with a high T2D risk had a higher risk of depressive symptoms (women: 1.71, 1.05-2.81; men: 2.23, 1.22-4.05) and anxiety symptoms (women: 1.84, 1.03-3.29; men: 2.73, 1.09-6.81). No statistically significant interactions between sex and T2D risk were observed regarding the included health outcomes. Conclusions A high T2D risk is associated with a lower probability of a favourable SRH and SRMH and a higher risk of depressive and anxiety symptoms in men and women. The underlying mechanisms need further identification, in order to design synergistically beneficial health promotion for cardiometabolic and mental health. Key messages • No sex-specific differences in general and mental health were found in people at high T2D risk. • Further research is needed to identify the underlying mechanism to improve general and mental health.

Direct IL-6 inhibition prevents arterial thrombosis by reducing collagen-mediated platelets activation

Abstract Introduction Interleukin 6 (IL-6) has a pivotal role in atherothrombosis. Yet, targeting IL-6 to prevent atherothrombotic events still requires validation of efficacy and safety. The recent phase 2 RESCUE trial reported that direct inhibition of IL-6 ligand by the monoclonal antibody (mAb) Ziltivekimab is safe in patients with elevated cardiovascular risk. Purpose This project investigated the effects of direct IL-6 inhibition on arterial thrombosis, and assessed the underlying cellular mechanisms. Methods Three month old C56Bl/6 male mice received very-low dose LPS i.p. for 4 weeks. During the last week they were randomized to receive in addition either anti-mouse IL-6 mAb 200 μg i.p. every other day or IgG1 isotype control. Then thrombosis of left common carotid artery (LCCA) was induced by laser injury under anesthesia. Platelets of treated mice were isolated and stimulated with either adenosine di-phosphate (ADP), collagen-related peptide (CRP) or thrombin receptor activating peptide (TRAP). Platelets activation was measured by flow-cytometry, as expression of P-selectin and JON/A.The effect of direct IL-6 inhibition was confirmed in patients with stable coronary artery disease (sCAD) by ex-vivo incubation of isolated platelets with either anti-human IL-6 mAb 1.5 μg/mL or IgG1 isotype control. Platelet activation was measured by flow-cytometry, as expression of P-selectin. Results Mice treated with anti-IL6 antibody displayed a significantly longer time-to-occlusion after the LCCA (Figure 1), without any significant difference in coagulation parameters. After stimulation with CRP, platelets were significantly activated in control mice, but not in mice treated with anti-IL6 mAb. Similarly, activation of isolated platelets from patients with sCAD was significantly reduced (Figure 2) by the ex-vivo treatment with anti-IL6 mAb. Conclusion The direct inhibition of IL-6 reduces platelets reactivity to collagen, thereby blunting arterial thrombosis upon endothelial damage. These results provide a potential mechanism to explain the reduction of cardiovascular risk associated to direct IL-6 inhibition. Conclusion The direct inhibition of IL-6 reduces platelets reactivity to collagen, thereby blunting arterial thrombosis upon endothelial damage. These results provide a potential mechanism to explain the reduction of cardiovascular risk associated to direct IL-6 inhibition.Figure 1Figure 2

Radon Exposure Is Associated with Breast Cancer Risk: A Long-Term Population-Based Study from Finland

Abstract Background Radon is a common environmental carcinogen. It is not known whether radon exposure and breast cancer risk are associated at the population level. Methods Women continuously living in Finland during the 1987-2016 period were linked to municipality-level indoor radon data annually to estimate their cumulative radon exposure over 30 years. Breast cancer incidence was observed over five years from 2017 onwards. Association between radon exposure and breast cancer incidence was assessed using conditional Cox models adjusted for family history of breast cancer, reproductive history, and socio-demographic covariates. Population attributable fractions (PAF) of breast cancer due to radon exposure were estimated. Robustness analyses were conducted in the population who lived only in houses. Results Among 1,335,947 women, 20,067 breast cancer cases were observed during a median follow-up period of 4.9 years. Among women who were exposed to high levels of radon (>100 Bq/m3), overall breast cancer incidence was 10% higher (Hazard ratio 1·10 [95% CI 1·05-1·16]), duct carcinoma incidence was 6% higher (1·06 [1·00-1·13]), lobular carcinoma incidence was 8% higher (1·08 [0·94-1·23]), and the incidence of other morphological sub-types was 34% higher (1·34 [1·17-1·53]) than among other women. Robust associations with overall breast cancer incidence (1·12 [1·05-1·20]) and the incidence of morphological sub-types in the house sample. Correspondingly, suggestive dose-response associations were observed. Conclusions High radon exposure is associated with elevated breast cancer risk at the population level, and this relationship is independent of well-established risk factors. Key messages • This study investigates the association between long-term radon exposure and breast cancer incidence based on national register data. • High radon exposure is robustly associated with breast cancer risk in general Finnish population.

Cardiac risk confrontation in primary care as a teachable moment towards improved health outcomes

Abstract Background Urgent life events, such as acute coronary events, can evoke a teachable moment (TM) for lifestyle change. This study aims to investigate whether less urgent events, such as being confronted with an increased risk of cardiovascular disease, can evoke a TM, what psychosocial factors are associated with it, and whether experiencing such a TM predicts improved health outcomes. Methods The study included 114 patients who were informed about their elevated cardiovascular risk during a primary care visit. Participants completed a survey assessing whether they experienced a TM and several psychosocial factors linked to experiencing it: perceived risk, affective impact, changed self-concept. Participants monitored their weight and blood pressure for six months using an at-home self-monitoring device. Univariate and multivariate regression analyses were conducted to examine the associations between the psychosocial factors and the lifestyle change intentions with changes in blood pressure and weight. Results Of the participants, 55.3% experienced increased lifestyle change intentions. Lower risk perception ((B = -0.27; CI = -0.39-(-0.15)) and higher change in self-concept (B = 0.34; CI = 0.23-0.44) were associated with higher intention to change lifestyle. Higher risk perception (B = 0.23; CI = 0.06-0.42) and higher change in self-concept (B = 0.54; CI = 0.37-0.72) predicted a lower weight reduction at six months. A higher change in self-concept predicted a higher blood pressure reduction (B = -3.32; CI = -6.55-(0.09)). Lastly, a higher lifestyle change intention predicted bigger reductions blood pressure (B = -5.04; CI = -9.08-(-0.29)). Conclusions Results suggest that less urgent cardiac events, such as a confrontation with an increased cardiac risk, can be experienced as a TM that urges lifestyle change intentions and affects health outcomes. Risk confrontations in primary care therefore offer a unique opportunity to provide lifestyle counseling at the right moment. Key messages • A confrontation with an increased cardiac risk in primary care can be experienced as a teachable moment. • Experiencing a teachable moment after a cardiac risk confrontation in primary care affects health outcomes.

Long term follow up of Implantable Cardioverter Defibrillators (ICD) in hypertrophic cardiomyopathy: is subcutaneous the way forward?

Abstract Introduction Young patients have greater risks of longer-term complications including inappropriate therapy (IT) from Implantable Cardioverter Defibrillators (ICD) than older ICD patients. In prevention of sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HCM), these complications are critical in determining treatment thresholds. When comparing transvenous ICDs (TV), subcutaneous ICDs (SICD) may have different risks & benefits that define their relative utility. We investigated TV & SICD outcomes in a propensity matched cohort of HCM patients. Methods We used electronic health records in a retrospective study of HCM patients receiving an ICD between 2006-22 at tertiary centre. Indications for ICD implantation, including type of device, were determined by the treating cardiomyopathy team according to ESC guidance. All TV device types were included & eligibility for SICD included passing screening in at least 1 sensing vector. Outcome data included patients lost to follow-up until the last device check & patients who had both device types were included twice. Patients were censored after their first IT for an analysis of IT, & their first ‘ICD complication’ for that analysis. ICD complications are defined as all other complications that resulted in a re-intervention procedure (excl SICD battery advisory), or extra procedure at box change. The audit was registered with local institutional review board for ethical approval. Propensity scoring was used for stratification and covariate adjustment. Matching was conducted using the 12 baseline variables. Associations with IT, ICD complications and their composite were assessed using proportional hazard regression (Cox) models, with time to event starting at implant date. Univariable & multivariable regression analyses were used as appropriate. Hazard ratios (HRs) of 95% confidence intervals were estimated by fitting a model with the propensity score and dichotomous variable (TV vs SICD). A p value of <0.05 was considered statistically significant. Analyses were conducted using R- Version 2023.06.0+421. Results Mean age was 55±14.2 years with follow-up of 73±63 months; 70.7% were male. Of a total of 611 patients, with 469 in the TV group & 164 in the SICD. SICD patients had fewer complications, with no differences in IT across all and propensity matched analyses (CI 0.64), fig 1. Conclusion In HCM, when compared to TV, SICDs are associated with fewer ICD complications & not associated with more frequent IT. Intriguingly, there was a higher rate of IT with the first generation SICD, causing the wide IT errors at longer durations. Complications over long term follow up require more assessment, but the absence of TV lead intervention creates reduced risks for SICD complications. In HCM patients without pacing needs, SICDs may be preferred for HCM-SCD prevention. In addition, the lower risks associated with SICD could lead to lower treatment thresholds for people with elevated lifetime HCM-SCD risk.

Mortality risk in patients with carotid artery disease undergoing carotid endarterectomy compared to the general population

Abstract Background Patients with carotid artery disease undergoing carotid endarterectomy (CEA) appear to be at high risk of all-cause mortality during their follow-up. However, the possible predictors of this adverse outcome are not elucidated yet. Purpose We aimed to test cardiovascular (CV) risk factors as possible predictors of all-cause mortality in patients undergoing CEA and to determine whether there is a difference between the mortality rate of our study cohort and the general population. We hypothesize that CEA-treated patients have a higher mortality rate during follow-up after surgery than the general population, which is not related to the presence of CV risk factors. Methods We prospectively enrolled and followed up patients undergoing CEA. Univariate and multivariable Cox regression were performed to test whether common CV risk factors (demographics, laboratory values, comorbidities, and events before CEA) were predictive of all-cause mortality. We then compared the standardized mortality ratio (SMR) of our population and the age-sex-matched Minnesota (MN) general population at 5,10, and 21 years of follow-up after CEA. Results A total of 710 patients were followed for a median of 7.1 [2.9-11.9] years after CEA. Mortality occurred in 198 (27.0%) patients during the follow-up. The median time to event was 11.0 [10.0-12.0] years. Age was the only predictor of all-cause mortality in CEA-treated patients in multivariable models adjusted for known CV risk factors (Model 1: HR 1.03 [95%CI 1.01-1.06]; p=0.004; Model 2: HR 1.02 [95%CI 1.00-1.04]; p=0.023) (Table 1). However, the CEA-treated group had a higher mortality rate than would have been expected in the MN population (log-rank p<0.001) (Fig.1A). Compared to the MN population, at 5 years of follow-up only patients <60 years old had a higher SMR (4.53 [1.95-8.92]; p=0.001), whereas, at 10 years and 21 years of follow-up, our study population had a higher mortality rate at any age (Fig.1B). Conclusions The elevated mortality risk post-CEA in our cohort cannot be solely attributed to chronological aging. The underlying process of atherosclerosis likely contributes to all-cause mortality, and plaque characteristics may offer additional insight into the risk stratification of this patient group.All cause mortality predictors after CEAStudy population vs. MN population SMR

Active surveillance for cardiac complications after major noncardiac surgery: implications on resource utilization and safety in high-risk patients

Abstract Background The 2022 ESC guidelines on cardiovascular assessment and management of patients undergoing noncardiac surgery recommend that high-risk patients should undergo active surveillance for cardiac complications, including perioperative myocardial infarction/injury (PMI), following major noncardiac surgery. Unfortunately, little is known about the resource use and safety of active surveillance compared to a control cohort (i.e. without active surveillance). Objective To quantify the impact of active surveillance for cardiac complications, by perioperative cardiac troponin (cTn) measurements and a systematic PMI work-up on working days, on resource usage and safety. Methods We did a retrospective comparison of non-randomised pre- vs post-implementation of an active surveillance program for cardiac complications in patients at elevated cardiovascular risk undergoing noncardiac surgery at two hospitals in Switzerland. The two cohorts' resource use and safety were compared. Resource use encompassed perioperative cTn measurements, ECGs, cardiac imaging, cardiology consultations as well as coronary angiography (CAG) and revascularisation procedures. Safety was assessed based on the number of "seemingly normal CAG" and complications arising from CAG and revascularisation procedures. Results A total of 13’147 patients, 10’346 in the active surveillance cohort and 2’805 in the standard-of-care (SOC) cohort, were eligible for this analysis. Patient characteristics between both cohorts were comparable (e.g. median age of 74 vs 73 and 44.8% vs 43% female, respectively). Patients in the active surveillance cohort underwent significantly more perioperative cTn measurements (86.4% vs 3.5%, respectively), postoperative ECGs (13.5% vs 5.7%), postoperative cardiac consultations (5.9% vs 2.4%), postoperative transthoracic echocardiogram (TTE) (7.5% vs 6.1%), postoperative myocardial perfusion imaging (MPI) (1.2% vs 0.6%), and postoperative CAG (0.8% vs 0.4%, all p <0.05). The increased resource use led to a substantial increase in detected cardiac complications within the first 48h after surgery: active surveillance 1’207 (12%) (95%CI 11%-12%) vs SOC 68 (2.4%) (95%CI 1.9%-3.1%). The active surveillance cohort generated an overall cardiac management cost of 236 Euros (95%CI 223–250) per patient vs 133 Euros (95%CI 110–160) per patient in the SOC cohort, resulting in an incremental cost for the active surveillance of 103 Euros (95%CI 110–160) per patient. Thereby the cost of detecting one additional cardiac complication within 48h was 989 Euros. Concerning safety, no significant differences in the number of "seemingly normal CAG" (6.4% vs 15%, p=0.1) and complications due to CAG and revascularisation (0.6% vs 5.1%, p=0.08) were observed. Conclusion The active surveillance for cardiac complications is safe when compared to a standard-of-care cohort while 989 Euros per additional detected cardiac complication seems reasonably priced.Resource-utilization tableOverview

Interactive effects of outdoor fine particulate matter and metabolic, behavioural, and psychosocial risk factors on cardiovascular disease: analysis of the PURE-China cohort study

Abstract Background Long-term PM2.5 exposure has been associated with an elevated risk of cardiovascular disease (CVD) and its associated risk factors.[1–4] There is a paucity of studies investigating the interactive effects of PM2.5 exposure and a comprehensive list of risk factors including metabolic, behavioural, and psychosocial risk factors on CVD risk.[5] Purpose This study aims to examine the interactive effects of PM2.5 exposure and metabolic, behavioural, and psychosocial risk factors on incident CVD. Methods The Prospective Urban Rural Epidemiology (PURE)-China cohort study is a population-based cohort study recruiting participants aged 35–70 years from 115 communities in 12 provinces of China between 2005 and 2009, and followed up until August 31, 2021.[6] Participants’ metabolic, behavioural, and psychosocial risk factor information was recorded. PM2.5 concentrations were extracted from a 1x1 km2 global model.[7,8] For this analysis, we included participants aged 35–70 years at baseline without a history of CVD, with at least one follow-up visit. The primary outcome was a composite of major cardiovascular events (CVD deaths, myocardial infarction, stroke, and heart failure). Additive interaction was measured by relative excess risk due to interaction (RERI), the proportion of disease attributable to interaction (AP), and the synergy index (SI).[9,10] To comply with the additive interaction method, we classified concentrations of PM2.5 into low and high levels by the median of 3-year average PM2.5 concentration (45.7 μg/m3, IQR: 33.7-74). Cox proportional hazard models were used to assess the associations of metabolic, behavioural, and psychosocial risk factors on incident CVD by PM2.5 concentrations. Results The PURE-China study recruited 47 931 participants, of which 39 329 are eligible for this analysis. During the median follow-up period of 11.9 years (IQR: 9.6-12.6), 1462 and 2155 major CVD events had occurred in the low and high PM2.5 group respectively. There was a synergistic interaction between PM2.5 and the systolic blood pressure (SBP) for CVD: RERI: 0.363, 95% CI: 0.196-0.531; AP: 0.098, 95% CI: 0.081-0.115; SI: 1.155, 95% CI: 1.132-1.177; high LDL cholesterol: RERI: 0.219, 0.003-0.436; AP: 0.135, 0.008-0.263; SI: 1.549, 0.947-2.533. A significant synergistic interaction was also identified between PM2.5 and household air pollution (RERI: 0.457, 0.292-0.622; AP: 0.277, 0.184-0.37; SI: 3.362, 1.409-8.019). Interactions between PM2.5 and low grip strength on CVD were significantly synergistic, but antagonistic between PM2.5 and low physical activity (RERI: -0.248, -0.485--0.012; AP: -0.174, -0.349-0.001; SI: 0.633, 0.412-0.971). Conclusion Addictive interaction was between PM2.5 and SBP, high LDL cholesterol, household air pollution, low grip strength and low physical activity on incident CVD, indicating the benefit of coordinated control strategies for metabolic, physical, and environmental risk factors for the prevention of CVD.

Examining the link between age of alcohol initiation, adolescent alcohol use and adult substance use

Abstract Background Understanding the relationship between adolescent alcohol use and adult substance use is important for prevention programmes. Existing evidence presents divergent findings and potential mechanisms are debated. Methods We estimated associations between the age of alcohol initiation and alcohol use at age 17 and substance use at age 20 in a nationally representative cohort (n = 4554). Weighted logistic regression models were fitted using Generalised Estimating Equations in multiply imputed and complete case data. Results Our analysis identified that 27% of participants reported first alcohol use at ≤ 14 years old, with 37% engaging in risky alcohol use by age 17. At age 20, 14% reported hazardous alcohol use, while 38% used tobacco, 24% cannabis, and 28% other drugs. The age at which alcohol was initiated and risky alcohol use at 17 years old were both strongly associated with alcohol, tobacco, cannabis and other illicit drug use at 20 years old. Sequential change in effect estimates coupled with non-overlapping confidence intervals suggest a dose-response relationship between age of alcohol initiation and tobacco and other drug use at age 20. Conclusions First use of alcohol at 14 or younger was common. Earlier alcohol initiation and risky alcohol use are each associated with substantially elevated risk for substance use at 20 years old even after accounting for common liability factors. Acknowledgement: Growing Up in Ireland (GUI) is funded by the Department of Children, Equality, Disability, Integration and Youth (DCEDIY). It is managed by DCEDIY in association with the Central Statistics Office (CSO). Results in this report are based on analyses of data from Research Microdata Files provided by the CSO. Neither the CSO nor DCEDIY take any responsibility for the views expressed or the outputs generated from these analyses. Key messages • Delaying alcohol initiation and preventing risky alcohol use during adolescence may reduce levels of substance use in young adults. • Self-reported early use of alcohol remains common.

Lipoprotein(a) regulates vascular redox state and inflammatory response in patients with coronary artery disease

Abstract Background Circulating Lipoprotein(a) (Lp(a)) is associated with cardiovascular disease, and over 90% of its variation in plasma is genetically determined. However, neither the causal nature of this association nor the underlying mechanisms are fully documented. Purpose We explored the hypothesis that Lp(a) triggers atherogenesis by dysregulating vascular redox-sensitive inflammatory state. Methods 1027 patients with advanced coronary artery disease (CAD) undergoing cardiac surgery were genotyped and a genetic signature (LPA) determining Lp(a) levels was generated. RNA-sequencing and vascular superoxide (O2.-) measurements were performed in internal mammary arteries (IMA), and the contribution of NADPH-oxidases and uncoupled endothelial nitric oxide synthase (eNOS) were determined. Patients were followed up for a median of 5.07 years. Results A genetic screening identified 7 SNPs (LPA) that were associated with increased Lp(a) plasma levels (A). Patients in the alternative LPA variant group, as well as patients with higher plasma Lp(a) levels, had significantly higher basal arterial O2.-. Patients with diabetes had significantly lower plasma Lp(a) compared to non-diabetics and the association between plasma Lp(a) and arterial O2.- was driven by non-diabetic patients. The effect of Lp(a) on vascular redox state was primarily due to eNOS uncoupling, resulting from reduced vascular tetrahydrobiopterin (BH4) bioavailability. Indeed, patients in the alternative LPA variant group or with higher plasma Lp(a) levels had a greater arterial eNOS-derived (LNAME-inhibitable) O2.- production (B,C). Levels of eNOS essential cofactor BH4 (defined by the ratio of plasma BH4 to its oxidation product BH2) were lower in patients with higher plasma Lp(a) levels (D). There was no significant impact of Lp(a) variability on vascular NADPH oxidase-derived O2.-. RNA sequencing of arterial tissue revealed dysregulation of nitrosative and inflammatory signalling in patients with high Lp(a), although there was no association with systemic biomarkers of inflammation (i.e. hsCRP) or oxidative stress (i.e. malondialdehyde). Finally, both LPA and high plasma Lp(a) were associated with elevated risk for cardiovascular mortality (E,F). When the cox regression models were additionally corrected for arterial O2.- production, both the models for the LPA genetic signature (HR[95% CI]=2.053[0.180-23.428], p=0.563) and plasma Lp(a) (HR[95% CI]=1.700[0.325-8.885], p=0.529) lost significance. This implies that redox-sensitive inflammatory signalling may be a link between Lp(a) and cardiovascular risk. All above associations were independent from plasma ApoB. Conclusions This study demonstrates for the first time that a genetically determined increase in plasma Lp(a) results in dysregulated vascular redox/nitrosative signalling in patients with atherosclerosis, revealing new therapeutic opportunities in cardiovascular prevention.

Risks of high temperature exposure on infectious diseases in Portuguese hospitals

Abstract Background The convergence of climate change and infectious diseases presents a growing public health challenge. As global temperatures continue to climb, the geographical spread of climate-sensitive diseases is shifting, underscoring the necessity for comprehensive early warning systems grounded in a One Health framework. Methods This retrospective observational study analyzed daily maximum temperature from May to September, between 2000 and 2018, in mainland Portugal, at a county level, obtained from a European-level gridded observations dataset. Hospital admissions with a primary diagnosis of infectious and parasitic diseases were sourced from the Hospital Morbidity Database. A distributed lag non-linear model was developed to estimate the immediate and lagged relative risks (RR) of temperature exposure on admissions, focused on a lag of 10 days. Results Our research reveals a 16% (95% CI: 9% - 23%) rise in the RR of hospital admissions due to infectious and parasitic diseases after exposure to extremely high temperatures (39 °C). This elevated risk persists for up to 2 days following exposure, with the second day exhibiting the largest increase at 53% (31% - 80%). Furthermore, our findings indicate a subsequent resurgence in RR, reaching 6% (2% - 11%) 9 days after exposure. Conclusions Our results highlight a short-term effect of extreme temperature exposure on infectious and parasitic disease admissions. This data provides valuable insights to guide policymakers in identifying critical periods of vulnerability and implementing this knowledge into heat early warning systems, contributing to developing effective public health strategies against climate change. Acknowledgments The authors thank Fundação para a Ciência e a Tecnologia (FCT, Portugal) for research grant UIDP/04923/2020 and NOVA National School of Public Health for access to the Hospital Morbidity Database made available for research purposes by Administração Central do Sistema de Saúde, IP (ACSS). Key messages • Exposure to extremely high temperatures increases the risk of admission due to infectious and parasitic diseases by 16%, with a peak occurring two days after exposure. • This data is essential for policymakers to identify and integrate vulnerable periods into early heat warning systems, enhancing effective public health strategies against climate change.

Association of Altitude with Mortality among Patients with Hypertension - A Cohort Study

Abstract Background Available evidence falls short in assessing the risk of all-cause mortality and cardiovascular disease (CVD) mortality among individuals with hypertension residing at various altitudes. This study’s objective was to investigate the correlation between residential altitude and the rates of all-cause mortality and CVD mortality among hypertensive patients. Methods This prospective cohort study encompassed 67,275 hypertensive individuals aged 35 years and above in the year 2018. Participants were categorized into four distinct groups based on their residence altitude: those living below 500 meters, between 500 and 1499 meters, 1500 to 2500 meters, and above 2500 meters. The study spanned a mean follow-up duration of 4.78 years. The associations between residential altitude and the risks of all-cause and CVD mortality were analyzed using Cox proportional hazards regression models. Results Among the 67,275 hypertensive patients included in the study (mean age of 63.9 years, with 45.3% being male), 8,768 deaths were recorded, of which 5,666 were attributed to CVD. Following multivariate adjustment, when compared to the group residing at altitudes below 500 meters, the groups living at altitudes of 500-1499 meters, 1500-2500 meters, and above 2500 meters exhibited significantly elevated risks of all-cause mortality [hazard ratio, HR = 1.45 (95% CI: 1.36-1.54), 1.35 (95% CI: 1.36), and 1.41 (95% CI: 1.28-1.54), respectively] and CVD mortality [HR = 1.47 (95% CI: 1.35-1.58), 1.42 (95% CI: 1.33-1.52), and 1.46 (95% CI: 1.31-1.62), respectively]. For each 500-meter increment in altitude, the risk of all-cause and CVD mortality increased by 10% and 11%, respectively. Subgroup analyses and sensitivity assessments consistently supported this association. Conclusions This study’s findings indicate a substantial connection between long-term residential high-altitude exposure and increased risks of all-cause mortality and CVD mortality among individuals with hypertension. Key messages • Increased altitude of residence increases the risk of subsequent all-cause and CVD mortality in hypertensive patients. • This study highlights that relevant guidelines and healthcare providers should consider altitude as an important factor in reducing the burden of hypertension and CVD.

Complete revascularisation versus culprit lesion only PCI in patients with non-ST-elevation myocardial infarction and multivessel disease.

Abstract Background The incidence of non-ST-elevation myocardial infarction (NSTEMI) is escalating, with patients diagnosed with multivessel disease (MVD) facing more adverse clinical outcomes. Yet, optimal treatment strategies for NSTEMI patients with MVD remain uncertain. Objectives This study aimed to assess the clinical outcome of NSTEMI patients with MVD who underwent complete revascularization compared to those treated with the culprit lesion only. Methods Between 2014 and 2017, patients presenting with NSTEMI and MVD undergoing successful percutaneous coronary intervention (PCI) were retrospectively included. MVD was defined as patients having more than one lesion considered angiographically significant, exhibiting at least 50% stenosis of the vessel diameter on visual estimation, or having a Coronary Angiography-Derived Fractional Flow Reserve (caFFR) measurement of 0.80 or less. The main exclusion criteria were single vessel disease, and previous coronary-artery bypass grafting surgery. The primary endpoint of this study was major adverse cardiac events (MACE) at 3 years, defined as a composite of cardiac death, myocardial infarction, and ischemia-driven revascularization. Results A total of 358 patients were included (mean age: 67.34±12.77; male: 70.1%), 155 and 203 patients were stratified into complete revascularisation group and culprit-lesion-only PCI group respectively. During 3-year follow-up, the culprit-lesion-only PCI group exhibited a significantly elevated risk of MACE compared to the complete revascularization group (17.7% vs 7.74%; hazard ratio [HR] 2.412, 95% confidence interval [CI] 1.255 - 4.636, P = 0.008). The increase 3-year MACE rate was mainly driven by the higher rate of ischaemia-driven revascularization in the culprit-lesion-only PCI group (11.3% vs 3.23%, HR 3.637, 95% CI 1.383 - 9.566, P = 0.009). Conclusion In NSTEMI patients with MVD, complete revascularization was superior to culprit-lesion-only PCI in mitigating the risk of future MACE at 3 years, which is predominantly attributed by a reduced incidence of repeat revascularisations.

Predictive value of cardiac 18F-fluorodeoxyglucose positron emission tomography for fatal ventricular arrhythmic events in patients with cardiac sarcoidosis

Abstract Background Patients with cardiac sarcoidosis (CS) face an elevated risk of fatal ventricular arrhythmic events (FVAE), including sudden cardiac death. Late gadolinium enhancement (LGE) from contrast-enhanced cardiac magnetic resonance is used for diagnosis of CS and estimation of FVAE risk. However, its application is limited in cases with cardiac devices, renal failure or contrast agent allergies. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) emerges as a diagnostic tool for CS, even in cases where LGE is not feasible. Purpose This study aimed to investigate the potential utility of FDG-PET in predicting FVAE in patients with CS by hypothesizing that higher or lower percent FDG uptake could predict the FVAE risk. Methods Cardiac FDG-PET data from 121 patients with CS, acquired at our university hospital between March 2008 and November 2020, were analyzed. A polar-map model was used to calculate percent uptake relative to maximal cardiac FDG uptake in each of the American Heart Association (AHA) 17 segments (Figure A). Percent uptakes of the AHA 17 segments were compared between groups with and without future FVAE. LGE information was available in 82 patients and was used to assess the presence of LGE in regions where percent FDG uptake differed between the two groups. Results Among enrolled patients (mean age 59.5 ± 10.0 years, 67.8% women), 43 experienced FVAE following FDG-PET image acquisition. The group with future FVAE had a higher history of FVAE (7.7% vs. 37.2%) and beta-blocker administration (38.5% vs. 60.5%), larger left ventricular diastolic diameter (LVDd) (49.3 ± 7.3 mm vs. 57.4 ± 9.5 mm) and lower ejection fraction (LVEF) (56.6 ± 13.6% vs. 42.0 ± 15.2%) compared to the group without it (P < 0.05 all). Percent FDG uptake in the basal interventricular septum part (segment 3) (Figure A) was lower in patients with future FVAE compared to those without it (54.4 ± 13.8% vs. 41.8 ± 15.2%, P < 0.001 corrected for multiple comparisons). Kaplan-Meier analysis with a median split of percent FDG uptake in segment 3 showed that patients with lower uptake (<49%, N= 62) had lower FVAE-free survival compared to those with higher uptake (≥49%, N = 59) (P = 0.007) (Figure B). A Cox hazard model also demonstrated an association between percent FDG uptake in segment 3 and FVAE onset (hazard ratio 0.972 [95% CI 0.951, 0.995], P = 0.015) after adjusting for previous FVAE, beta-blocker administration, LVDd and LVEF. Similarly, analysis within the subgroup with LGE in the septum (N = 58) revealed a higher risk of FVAE in the group with lower percent FDG uptake compared to those with higher uptake (P = 0.020) (Figure C(a)). However, this association was not evident in patients without LGE in the septum (N = 24) (P = 0.821) (Figure C(b)). Conclusions Reduced percent FDG uptake with LGE in the basal intraventricular septum may serve as a valuable predictor of future FVAE occurrence in patients with CS.

Machine learning and traditional analysis of the interaction between cardiovascular diseases and hematological malignancies

Abstract Background Cardiovascular diseases and clonal hematopoiesis of indetermine potential (CHIP), the premalignant state of hematological cancers, exhibit reciprocal interactions. While the presence of CHIP confer a risk for heart failure, it is unclear if cardiovascular diseases are associated with elevated risk hematological cancers. Purpose To determine the association between cardiovascular diseases (CVD) and cardiovascular risk, and hematological cancer. Methods We evaluated 27,231 adults, free of CVD and cancer, who participated in preventive healthcare program between 2000-2018. Each participant underwent a complete physical evaluation, blood test and exercise stress test at baseline. CVD was defines as ischemic heart disease, stroke, atrial fibrillation or hypertension. Then, we used machine learning and traditional survival analysis to evaluate the association between CVD and hematological cancer. For machine learning, we used the random forest method using Curat package in r, and incorporated all continuous variables gathered into the model (70% training, 30% test). For survival analysis, we first matches each CVD patient to a control patient by propensity scores to balance for age, sex, smoking, diabeles mellitus, renal function, body mass index and length of follow-up. Then, we compared the CVD and non-CVD patients using cox proportional hazard regression. Results Using machine learning, we found that the strongest predictors for hematological cancer in our cohort are low eGFR, age, high atherosclerosis cardiovascular disease score (ASCVD) and BMI. Of note, systolic and diastolic blood pressure were also strong predictors of hematological cancer (Figure A). Then, we matched 5500 CVD patients to controls with median follow-up of 9.2 years (Interquartile range 5-15 years). During follow-up, 1380 developed cancer. Of them, 186 developed hematological cancer. We used cox proportional hazard regression and Kaplan Mayer method to determine the risk and hazard ratio of developing hematological cancer (Figure B-C). Compared with subjected without CVD, patients with CVD were 91% more likely to develop cancer during follow-up, and 62% more likely to develop hematological cancer (Figure C, HR=1.61. 95%CI 1.21-2.16). Moreover, the 10-year risk to develop hematological cancer was 1.9% for patients with CVD and 1.0% for individuals without CVD (Figure D). Notably, the increased incidence of hematological cancers included 38% increase in cases of leukemia but only 11% increase in cases of lymphoma. Conclusions Using machine learning and traditional analysis we show that CVD risk and CVD were associated with increased incidence of hematological cancer. Understanding this relationship could lead to advances in cardiovascular and cancer treatment and could ultimately help to improve patient outcomes.