Cardiovascular Disease Risk Research Articles

The association between the dietary salt intake and glucose intolerance in the non-diabetic populations: from the Korean National Health and Nutritional Examination Survey (KNHANES)

Abstract Background Diabetes is known to be a strong risk factor for cardiovascular disease (CVD), and controlling salt intake in patients with type 2 diabetes may be a strategy to reduce the risk of CVD. However, the clear interaction between salt intake and glucose homeostasis has yet to be investigated. Our study evaluated the frequency and risk of glucose intolerance (pre-diabetes) according to dietary salt intake in the non-diabetic population in Korea. Methods The Korean National Health and Nutritional Examination Survey (KNHANES) database was utilized for this study (https://knhanes.cdc.go.kr). A total of 72,751 subjects were enrolled in the KNHANES database from 2010 to 2018. The subjects were categorized into the following: normal fasting glucose (i.e., no pre-diabetes; FPG < 100 mg/dL), stage 1 pre-diabetes (FPG 100–109 mg/dL), stage 2 pre-diabetes (FPG 110–125 mg/dL). All subjects were divided into 8-equal groups according to their sodium intake: Group 1: ≤ 3.5 g, Group 2: 3.5 to 5.0 g, Group 3: 5.0 to 6.3 g, Group 4: 6.3 to 7.8 g, Group 5: 7.8 to 9.5 g, Group 6: 9.5 to 11.8 g, Group 7: 11.8 to 15.5 g, Group 8: > 15.5 g. This study is a retrospective cross-sectional study, so future risks cannot be assessed, but only the disease status assessment at the same time. Results Of the total 57,165 subjects without diabetes, 29.5% (16,874 subjects) were pre-diabetic, of which 22.0% (12,577 patients) were stage I pre-diabetic, and 7.5% (4,297 subjects) were stage II pre-diabetic. From the lowest salt intake group (group 1, salt intake <3.5g) to the highest salt intake group (group 8, salt intake>.5g), the pre-diabetes prevalence continuously increased from 22.9% to 33.3%. The range of stage 1 pre-diabetes was 16.4% to 26.4%, and the range of stage 2 diabetes was 6.5% to 8.7%. The odds ratio (OR) of pre-diabetic risk according to salt intake in the non-diabetic population, compared with group 1, group 2 was 1.16 (95% confidence interval [CI]: 1.07-1.25), group 3 was 1.32 (95% CI: 1.23 -1.43), group 4 was 1.46 (95% CI: 1.35-1.57), group 5 was 1.51 (95% CI: 1.40-1.63), group 6 was 1.57 (95% CI: 1.46-1.69), group 7 was 1.65 (95% CI: 1.53-1.78), group 8 was 1.68 (95% CI: 1.56-1.81). Conclusions High salt intake is significantly associated with pre-diabetes prevalence in the non-diabetic Korean population.

The association between the dietary salt intake and glucose intolerance in healthy populations: from the Korean National Health and Nutritional Examination Survey (KNHANES)

Abstract Background Diabetes is known to be a strong risk factor for cardiovascular disease (CVD), and controlling salt intake in patients with type 2 diabetes may be a strategy to reduce the risk of CVD. However, the clear interaction between salt intake and glucose homeostasis has yet to be investigated. Our study evaluated the frequency and risk of glucose intolerance (pre-diabetes) according to dietary salt intake in a healthy population in Korea. Methods The Korean National Health and Nutritional Examination Survey (KNHANES) database was utilized for this study (https://knhanes.cdc.go.kr). A total of 72,751 subjects were enrolled in the KNHANES database from 2010 to 2018. The subjects were categorized into the following: normal fasting glucose (i.e., no pre-diabetes; FPG < 100 mg/dL), stage 1 pre-diabetes (FPG 100–109 mg/dL), stage 2 pre-diabetes (FPG 110–125 mg/dL). All subjects were divided into 8-equal groups according to their sodium intake: Group 1: ≤ 3.5 g, Group 2: 3.5 to 5.0 g, Group 3: 5.0 to 6.3 g, Group 4: 6.3 to 7.8 g, Group 5: 7.8 to 9.5 g, Group 6: 9.5 to 11.8 g, Group 7: 11.8 to 15.5 g, Group 8: > 15.5 g. This study is a retrospective cross-sectional study, so future risks cannot be assessed, but only the disease status assessment at the same time. Results Of the total 36,782 healthy adults, 17.6% (6,481 subjects) were pre-diabetic, of which 14.7% (5,397 subjects) were stage I pre-diabetic, and 2.9% (1,084 patients) were stage II pre-diabetic. From the lowest salt intake group (group 1, salt intake <3.5g) to the highest salt intake group (group 8, salt intake>.5g), the pre-diabetes prevalence continuously increased from 9.2% to 22.8%. The range of stage 1 pre-diabetes was 7.3% to 18.3%, and stage 2 diabetes was 1.9% to 4.5%. The odds ratio (OR) of pre-diabetic risk according to salt intake in the non-diabetic population, compared with group 1, group 2 was 1.46 (95% confidence interval [CI]: 1.30-1.68), group 3 was 1.84 (95% CI: 1.62 -2.08), group 4 was 2.24 (95% CI: 1.99-2.54), group 5 was 2.43 (95% CI: 2.15-2.75), group 6 was 2.49 (95% CI: 2.20-2.81), group 7 was 2.83 (95% CI: 2.51-3.19), group 8 was 2.90 (95% CI: 2.57-3.27). Conclusions High salt intake is significantly associated with pre-diabetes prevalence in healthy Korean population.

Blockade of foam cell formation by an AP-1 inhibitor attenuates atherosclerosis in diabetes

Abstract Background Atherosclerosis is a major contributor to cardiovascular disease (CVD) related premature deaths in people with diabetes. Residual increased risk of CVD remains even after treatment of standard risk factors including hyperglycaemia. Therefore, there is an unmet clinical need of novel therapies that can directly target the intrinsic pathobiology of atherosclerotic plaque development. Macrophage associated pro-atherosclerotic processes including impaired cholesterol efflux resulting in foam cell formation are important therapeutic targets in atherosclerosis. Expression of genes linked to impaired cholesterol efflux can be regulated by multiple factors including transcription factors (TFs) such as activator protein 1 (AP-1) complex. Although, previous studies have implicated the role of foam cells in atherosclerosis, the role of AP-1 TF complex in foam cell formation in diabetes induced atherosclerosis is not known. Methods Diabetes was induced with streptozotocin (STZ) in atheroprone Apoe-/- mice and 10 weeks later aortae were subjected to single cell RNA sequencing (scRNA-seq) analysis using 10X Genomics platform. In vitro model mimicking diabetes-induced foam cell formation was established in human monocytes THP-1 derived macrophages using high glucose (25mM) and ox-LDL ± a small molecular inhibitor of AP-1, T-5224. AP-1 activity, gene expression and foam cell formation were assessed with activity assay, RT PCR and Oil Red O staining respectively in this setting. Complementary in vitro AP-1 knockdown experiments using shRNA were also performed. Furthermore, preclinical intervention studies were also performed where Apoe-/- mice made diabetic with STZ were treated 5-weeks post diabetes with T-5224 (30 mg/kg body weight daily for 5 weeks). Results scRNA-seq analysis identified a well-defined cluster of foam cells within macrophages with a diabetes specific proatherogenic transcriptomic profile. Differential gene expression analysis showed increased expression of AP-1 members cFos, Atf3, Atf4 and Junb exclusively in foam cell cluster in diabetes (cut off = FDR<0.05, Log2FC -2/2). Comparison with the ENCODE dataset for AP-1 target genes using Harmonizome version 3 showed that indeed multiple differentially expressed genes in diabetes were targets of AP-1. AP-1 members were also upregulated in the THP-1-based in vitro model of high glucose induced foam cell formation. THP-1 derived foam cells showed increased AP-1 activity and lipid uptake. Interestingly, AP-1 inhibition by T-5224 attenuated foam cell formation. AP-1 knockdown experiments validated experimental findings of AP-1 inhibition studies in THP-1 derived macrophages. Importantly, T-5224 treatment blocked foam cell formation resulting in reduced atherosclerosis in diabetic Apoe-/- mice in our intervention study design. Conclusion This study identified the AP-1 inhibition with T-5224 as a potential treatment for the diabetes induced foam cell formation and associated atherosclerosis.

Unveiling the heartbeat of hope: exploring cardiovascular morbidity, mortality, and socioeconomic threads in 65,173 Child, Adolescent, and Young Adult (caya) cancer patients

Abstract Background Despite significant progress in managing cancer in children, adolescents, and young adults (CAYAs), persistent complications impact their quality of life with some being severe or life-threatening.(1,2) Long-term outcomes depend on common risk factors for malignancy and cardiovascular diseases (CVD) that overlap, and treatments are known to increase the risk for CVD. (3,4) Healthcare inequality due to socioeconomic status is omnipresent and may significantly impact outcomes. Purpose This study aims to comprehensively cover morbidity, mortality, demographic, and socioeconomic factors among CAYAs and investigate their impact on cardiovascular outcomes. Methods This retrospective matched cohort study included the entire Swedish population under 25 with cancer from 1958 to 2021. The study population was identified from the National Board of Health and Welfare's Cancer Register, with controls paired 1:5 based on age, sex, and residence. Multiple registers provided data on morbidity, mortality, and demographics. Results Covering 63 years, identified 65,173 CAYAs (1.24 million patient-years) and matched with 312,935 controls (7.45 million person-years), a total of 378,108 individuals (74% females). The mean follow-up was 19.5 (SD16.9) years for CAYAs, and 23.8 (16.8) for controls, (p<0.001). At the end of the study, the median age of CAYAs was 33.4 (IQR 27.9) years and controls 39.2 (28.3) (p<0.0001), with an age span of <1-88 years in both groups. CVD was detected in 16.9 % of the CAYAs, representing a 1.21-time elevated risk (95% CI 1.18-1.23, p<0.0001) compared to controls. CAYAs had a higher mortality rate, and 5-years survivors lived a mean of 26.9 years shorter than controls. CV mortality was also increased in CAYAs, (1.9% compared to 0.7% in controls) but at a higher age, although at a mean of 22.8 years younger than their controls. The 5-year survivors were older at CV mortality and lived in mean 6.5 years shorter than controls (p<0.0001). After adjusting for socioeconomic factors, individuals born outside Europe and those with greater sick leave had a higher mortality risk, while education and marriage showed a beneficial association with mortality. (p<0.0001). Interpretation The Rebuc study, spanning six decades, revealed a significantly increased risk of serious complications among young cancer patients in Sweden. Not only do young cancer patient survivors face a significantly higher risk for cardiovascular disease, but the higher mortality risk before middle age also underscores the severity of the health challenges they confront. Furthermore, these young individuals are more susceptible to socioeconomic factors that may adversely affect their survival.

Impact of appendicular skeletal muscle mass on effect of intensive blood pressure control

Abstract Background Appendicular skeletal muscle mass (ASM) is associated with cardiovascular diseases (CVDs) and chronic kidney diseases (CKDs). However, whether low ASM affects the efficacy of intensive systolic blood pressure control is currently uncertain. Purpose To examine the impact of low ASM on the effects of intensive SBP control on cardiovascular and kidney outcomes. Methods Data from the Systolic Blood Pressure Intervention Trial (SPRINT) and the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trials was used. The primary outcome was a composite of myocardial infarction, acute coronary syndrome without myocardial infarction, stroke, heart failure, and cardiovascular death. The prespecified incident CKD was defined as a >30% decrease in estimated glomerular filtration rate to a value <60 mL/min/1.73 m2. Results A total of 14,017 patients were included in this study, 2203 (15.7%) of whom had low ASM. Over a median follow-up of 3.26 years, 1,032 primary outcomes and 460 incident CKD were observed. Patients with low ASM had a significantly higher risk of primary outcome and CKD. Intensive SBP control effects on cardiovascular outcomes were not significantly different on a relative scale or absolute scale. But low ASM significantly amplified the increased risk of CKD associated with intensive SBP control, on an absolute scale (P for interaction = 0.04). Conclusions Low ASM is one of the markers of increased risk of CVD and CKD, and it did not affect the cardiovascular benefits of intensive treatment, but significantly amplified the increased risk of CKD associated with intensive SBP control.

Cardiac biomarkers can detect and track subclinical HIV-associated myocardial disease in newly diagnosed people living with HIV

Abstract Background Cardiovascular disease (CVD) in people living with HIV (PLWH) remains poorly understood, and the profile of disease differs between high-income and low- and middle-income settings[1]. Subclinical cardiovascular abnormalities may be present at the time of HIV diagnosis and serve as potential substrate for future CVD[2]. Biochemical markers are fundamental in cardiac evaluation, and various novel assays have recently been discovered. Purpose To assess the presence and evolution of subclinical myocardial disease, we prospectively assessed the hearts of newly diagnosed PLWH and matched, HIV-uninfected controls using cardiac biomarkers and correlated our findings with cardiovascular magnetic resonance imaging (CMR). Methods Newly diagnosed, antiretroviral treatment (ART) naïve PLWH were recruited along with HIV uninfected, age- and sex-matched controls in the Western Cape Province of South Africa. All participants underwent measurement of high-sensitivity cardiac troponin T (hs-cTnT), N-terminal pro-B-type natriuretic peptide (NT-proBNP), soluble ST2 (sST2), Galectin-3, and a CMR study with multiparametric mapping. The HIV group started ART and was re-evaluated 9 months later. The cardiac biomarkers and their correlation with CMR parameters were evaluated in, and between groups. Results Compared with controls (n=22), hs-cTnT (4.0 ng/l vs 5.1 ng/l; p=0.004) , NT-proBNP (23.2 ng/l vs 40.8 ng/l; p=0.02), and Galectin-3 (6.8 ng/ml vs 9.0 ng/ml; p=0.002) were all significantly higher in the ART naïve group (n=73). After 9 months of ART, hs-cTnT (5.1 ng/l vs 4.3 ng/l; p=0.02) and NT-proBNP (40.8 ng/l vs 28.5 ng/l; p=0.03) both decreased significantly, and a trend of decrease was seen in sST2 (16.5 ng/ml vs 14.8 ng/l; p=0.08). Galectin-3 did not demonstrate decrease over time (9.0 ng/ml vs 8.8 ng/ml; p=0.6). The cardiac biomarkers that showed the best correlation with CMR measurements native T1, T2, and ECV, were NT-proBNP (rs≥0.4, p<0.001) and Galectin-3 (rs≥0.3, p<0.01). Conclusion Our cardiac biomarker data supports the presence of subclinical myocardial injury, remodelling, and fibrosis at HIV diagnosis and ART had a positive influence on these blood markers. It remains unclear if the underlying pathological processes were fully addressed by ART. The elevation of Galectin-3 despite ART may be indicative of ongoing cardiac remodelling that may incur future risk of CVD, and necessitates further study. The ability of cardiac biomarkers to detect and track tissue abnormalities diagnosed with CMR, showed promise. With additional research, this could lead to improvements in screening and monitoring myocardial abnormalities, even in CMR-limited settings.

Exploring the effects of reduced alcohol consumption on major adverse cardiovascular and cerebrovascular events in chronic heavy drinkers: a nationwide population-based cohort study

Abstract Background/Introduction Chronic heavy alcohol consumption is a well-established risk factor for cardiovascular disease (CVD), and the potential cardiovascular benefits of mild to moderate alcohol consumption need validation, particularly in the context of behavioral change from heavy drinking. Currently, there is a lack of research examining the potential benefits of reduced alcohol consumption in chronic heavy drinkers, specifically in relation to different subtypes of CVD. We hypothesized that habitual changes in alcohol consumption among chronic heavy drinkers would have a long-term prognostic effect on future CVD outcomes. Purpose We investigated the association between reduced alcohol consumption and the risk of major adverse cardiovascular and cerebrovascular events (MACCE) in chronic heavy drinkers. Methods From the Korean National Health Insurance Service-Health Screening database, we included a cohort of chronic heavy drinkers who underwent serial health examinations over two consecutive time-periods (first period: 2005–2008; second period: 2009–2012). Heavy drinking was defined according to the National Institute on Alcohol Abuse and Alcoholism criteria as >56 g/day or >196 g/week for men, and >42 g/day or >98 g/week for women. Overall, 13,854 heavy drinkers at baseline (mean age 55.84 ± 5.98 years; 91.6 % men) were categorized into two groups based on the alcohol consumption changes in the second period: sustained heavy drinking (n=9,403; 67.9%) or reduced drinking (n=4,451; 32.5%). The primary outcome was MACCE, a composite of nonfatal myocardial infarction or angina undergoing revascularization, any stroke accompanied by hospitalization, and all-cause death during follow-up. Results In this nationwide population-based cohort study, during a total follow-up of 107,102 person-years, the sustained heavy drinking group experienced a significantly higher incidence of MACCE than the reduced drinking group (incidence rate, 825 vs. 655 per 100,000 person-years; log-rank p=0.004). Reduced alcohol consumption was associated with a 28% lower risk of MACCE compared to sustained heavy drinking (adjusted-hazard ratio [HR]: 0.780, 95% confidence interval [CI] 0.656–0.928). These benefits were mostly driven by a significant reduction in the incidence of angina (adjusted-HR: 0.631, 95% CI 0.425–0.926) and ischemic stroke (adjusted-HR: 0.657, 95% CI 0.472–0.914). The preventive effects of reduced alcohol intake were consistently observed across various subgroups of heavy drinkers, except for smoking status (p-interaction=0.015) and even after including abstainers in the sensitivity analysis. Conclusion Reduced alcohol consumption in heavy drinkers could lower the future risk of CVD, with the most pronounced benefits expected for stable/unstable angina and ischemic stroke. Further research is warranted to explore the optimal strategies for promoting sustained reductions in alcohol intake.Cumulative MACCE incidence curves

Body weight variability as a predictor of cardiovascular outcomes in type 1 diabetes: A nationwide cohort study.

Intraindividual body weight variability (BWV), that is, the degree of weight fluctuations over time, is associated with an increased risk of cardiovascular diseases (CVDs) in multiple settings. The impact of BWV on cardiovascular risk in type 1 diabetes (T1D) remains unclear, despite the issues relative to weight management in individuals with this condition. Using data from the Swedish National Diabetes Register, we identified individuals with T1D and without CVD at baseline with at least three measurements of body weight taken over three consecutive years. We estimated BWV as quartiles of the standard deviation of weight measures and explored its longitudinal association with the incidence of CVD during a 12.7 ± 4.6 year follow-up through adjusted Cox regression models. The primary endpoint was the composite of nonfatal myocardial infarction, nonfatal stroke and all-cause mortality. We modelled the function of risk in relation to the magnitude of BWV, testing also whether weight trends, that is, increasing, stable or decreasing, age, sex and glycaemic control modified the association between BWV and the outcome. Among the 36 333 individuals with T1D in the register, we identified 19 373 individuals with at least three measures of body weight and without CVD at baseline. Participants with the highest BWV had a 42% increased risk of reaching the primary endpoint compared to those with the lowest BWV (hazard ratio [HR] = 1.42, 95% confidence interval [CI]: 1.24-1.62). In addition, high BWV was significantly associated with a 51% increased risk of all-cause mortality (HR = 1.51, 95% CI: 1.28-1.78), a 37% increased risk of peripheral artery disease (HR = 1.37, 95% CI: 1.06-1.77) and a 55% increased risk of hospitalization for heart failure (HR = 1.55, 95% CI: 1.20-2.01). BWV showed a quasi-linear association with the primary endpoint. No interaction was observed when comparing subgroups for weight trends, sex or degree of glycaemic control. In the subgroup of elderly individuals, the association of BWV with the primary endpoint was no longer significant. High BWV is associated with an increased risk of CVD and all-cause mortality in individuals with T1D, independently of canonical risk factors. Weight trends, sex and glycaemic control do not modify such association while older age attenuates it.

Cardiovascular events risk in office-masked nocturnal hypertension defined by home blood pressure monitoring: the J-HOP nocturnal blood pressure study

Abstract Background Elevated nocturnal home blood pressure (BP) has been reported to be associated with increased risk for cardiovascular disease (CVD). Masked hypertension defined by home BP monitoring is also a strong risk factor for adverse CVD outcomes. However, no study has investigated the association between office-masked nocturnal hypertension defined by home BP monitoring and CVD events risk. Purpose This study aimed to examine the association between office-masked nocturnal hypertension defined by home BP monitoring and CVD events risk in a clinical practice-based population. Methods This was a prospective observational study including Japanese participants with CVD or high risk of CVD. Three office BPs were taken on two different occasions. Nocturnal home BP was measured three times per night for two weeks. The association between office-masked nocturnal hypertension and incident total CVD events (including fatal and non-fatal stroke and coronary heart disease) was examined using Cox regression. Results 2,545 participants were followed for the mean of 7.1 years (18,116 person-years), during which 152 (6.0%) CVD events occurred. Mean age (standard deviation) was 63.3 (10.3) years; 49.0% were male; 82.6% took antihypertensive medications. The proportions of participants with normotension (office BP <140/90 mmHg and nocturnal home BP <120/70 mmHg), white-coat hypertension (office BP ≥140/90 mmHg and nocturnal home BP <120/70 mmHg), office-masked nocturnal hypertension (office BP <140/90 mmHg and nocturnal home BP ≥120/70 mmHg), and sustained hypertension (office BP ≥140/90 mmHg and nocturnal home BP ≥120/70 mmHg) were 25.3%, 14.4%, 23.2%, and 37.1%, respectively. The office-masked nocturnal hypertensive group and sustained hypertensive group had higher incidence rates of total CVD events compared with the normotensive group. Relative to normotension, those with both office-masked nocturnal hypertension (adjusted hazard ratio [aHR] 1.72, 95% confidence interval [CI] 1.01–2.92) and sustained hypertension (aHR 1.75, 95%CI 1.03–2.96) had similarly increased CVD risk, even after adjustment for daytime home BP values. Conclusions Screening for office-masked nocturnal hypertension with home BP monitoring identifies a potentially important group of patients with increased risk for incident CVD events for whom additional preventative measures may be appropriate.

Associations of smoking status with long-term cardiovascular events in different arterial territories: the EPIC Norfolk prospective population cohort

Abstract Background Smoking cessation is associated with a reduced risk of cardiovascular disease (CVD) events, mainly in ischemic heart disease (IHD) and stroke. However, the impact of smoking status (never, former or current smoking) on long-term CVD events across different arterial territories remains understudied. Knowledge of such associations is important, as it may assist in risk communication and smoking cessation motivation. We therefore investigated associations between smoking status and territory-specific CVD events in a large cohort with ≥20 years follow-up. Methods We included participants without baseline CVD from the European Prospective Investigation of Cancer (EPIC) Norfolk prospective population cohort. The strengths of associations between smoking, former smoking and never smoking with the first occurrence of a CVD event were evaluated using a competing risk-adjusted regression model. CVD events were defined as hospitalisation or death due to IHD, ischemic stroke, haemorrhagic stroke, peripheral arterial disease (PAD) or aortic aneurysm (AA). Patients were followed-up until the first event, non-CVD death (competing risk) or end of study (15-03-2018). The model was adjusted for sex, age, systolic blood pressure, low-density lipoprotein cholesterol (LDL-c), high-density lipoprotein cholesterol (HDL-c), diabetes, renal function and body mass index. We compared former and current smoking (at baseline) with never smoking. Results We included 23,581 participants (56% women) with a median baseline age of 58 years [interquartile range (IQR) 51-66]. During median follow up of 21.3 years (IQR 19.0-22.8), 26.4% experienced ≥1 CVD event. The first event of occurrence was IHD in 17.3%, ischemic stroke in 3.6%, haemorrhagic stroke in 1.4%, PAD in 3.1% and AA in 1.4%. Current (vs. never) smoking was associated with IHD [adjusted hazard rate (aHR) 1.53, 95% confidence interval (CI) 1.36-1.72], PAD (aHR 1.29, 95%CI 1.07-1.56) and AA (aHR 4.81, 95%CI 3.54-6.54). Current smoking was not significantly associated with ischemic stroke (aHR 1.20, 95% CI 0.95-1.52) and haemorrhagic stroke (aHR 1.18, 95% CI 0.81-1.70). In former (vs. never) smoking individuals, the association with AA remained statistically significant but less pronounced [aHR 1.69, 95%CI 1.29-2.23]. Conversely, former smoking was not associated with IHD (aHR 1.07, 95%CI 0.99-1.16) or PAD (aHR 1.09, 95%CI 0.95-1.26) (Figure 1). Conclusion After 20-years of follow-up, former smokers, compared to never-smokers, remain at considerably higher risk for CVD events, particularly for aortic aneurysm. This knowledge may assist in treatment decisions and risk communication.

Relationship between 3-dimensional aortic geometry and the risk of new-onset heart failure

Abstract Introduction Aortic geometric assessments to date have typically involved cross-sectional imaging of discrete aortic segments. However, the complex 3D geometry of the thoracic aorta, and its relationship to the risk of cardiovascular disease has not been assessed in large studies. Methods We segmented the thoracic aorta in SSFP axial MRI images from 49,282 UK Biobank participants using a deep convolutional neural network (U-Net). We then computed geometric measurements (centerline length, arch height, arch width, arch height-width ratio, arch unfolding index [inverse of tortuosity], curvature and mean, minimum and maximum diameters) in the overall thoracic aorta as well as in 6 subsegments. We quantified their relationship to the risk of cardiomyopathy and heart failure (HF) using multivariable Cox-proportional hazards models. All hazard ratios are standardized. Centerline length was allometrically indexed to body height. Results In models adjusted for age, sex, BMI kg/m2, low-density lipoprotein mg/dl, high-density lipoprotein mg/dl, triglycerides mg/dl, systolic blood pressure and diastolic blood pressure, the curvature of the aorta (HR=0.63; 95% CI=0.39, 0.99; P<0.05), particularly the aortic arch (HR=0.54; 95% CI= 0.35, 0.87; P<0.05) was strongly related to a lower risk of incident cardiomyopathy. A higher arch unfolding index (HR=1.46; 95% CI=1.03, 2.07; P<0.05), higher width-to-height ratio (HR=1.10; 95% CI= 1.02, 1.19; P<0.05) and lower aorta tortuosity (HR=1.20; 95% CI= 1.09, 1.32; P<0.05) were all associated with a higher risk of cardiomyopathy. This aortic geometric pattern was also associated with a greater risk of a new HF diagnosis (arch unfolding [HR=1.23; 95% CI= 1.07, 1.42; P<0.05], width to heigh ratio [HR=1.06; 95% CI= 1.01, 1.11; P0.05]). Conclusion We demonstrate that 3-D thoracic aortic geometric indices are strongly associated with incident cardiomyopathy and HF, independent of classic risk factors. This is likely related to abnormal afterload and ventricular-arterial interactions since adverse geometric remodeling affects left ventricular pulsatile load.Cardiomyopathy & Heart Failure Hazards

Loss of Y-chromosomal genes in macrophages induces paracrine phenotypic alterations in cardiac cells

Abstract Background At the intersection of gender medicine and ageing, mosaic loss of the Y chromosome (mLoY) in hematopoietic cells has emerged as a novel cardiovascular risk factor. As the most prevalent chromosomal aberration in men, mLoY is age-associated and characterised by interindividual varying frequencies of LoY cells in blood. It is associated with an increased risk for cardiovascular disease and mortality. A murine model of mLoY demonstrates myocardial fibrosis and reduced lifespan. However, the interactions between LoY hematopoietic and cardiac cells remain elusive. It is uncertain, whether the loss of single genes or combinations of multiple genes drive the observed effects, impeding the development of targeted therapies. Purpose We aimed to examine the impact of individual Y-chromosomal genes in macrophages concerning their paracrine effects on cardiac cells types. Methods and results To identify target genes, we analysed two single-nuclei RNA sequencing datasets of patient-derived PBMCs and THP-1 monocytic cells for their expression of Y-chromosomal genes. We identified nine genes that exhibited robust and concordant expression in both datasets. Seven were protein coding (RPS4Y, DDX3Y, EIF1AY, ZFY, UTY, USP9Y and KDM5D) and two were non-coding (TTTY14 and LINC00278). Using siRNA pools, we achieved >50% reductions in mRNA content in THP-1 M0 macrophages for all genes (p<0.05) and collected conditioned media (CM). As previous data suggested increased myocardial fibrosis in mLoY, we assessed the impact of CM on primary human cardiac fibroblasts. Notably, treatment with CM from ZFY, TTTY14 or LINC00278 silenced macrophages induced collagen 1A1 protein expression by 1.44-, 1.30- and 1.86-fold, respectively (all p<0.05), suggesting that loss of these genes might contribute to myocardial fibrosis. To explore potential effects on cardiomyocytes, neonatal rat cardiomyocytes were exposed to CM. We observed reduced beating frequencies upon treatment with CM from ZFY, TTTY14 or UTY silenced macrophages (relative fold-changes 0.45, 0.40, 0.53, respectively; all p<0.05). While suggestive of cardiomyocyte stress, we found no changes in the expression of the stress markers Nppa or Nppb, possibly indicating direct effects on ion transporters. Given the strong association of cardiovascular disease with endothelial cell dysfunction, we investigated the effects of CM on human umbilical vein endothelial cells (HUVEC). CM from ZFY and KDM5D silenced macrophages induced ICAM protein expression in HUVEC by 1.9- and 1.6-fold, respectively (both p<0.05). Conclusion Loss of individual Y-chromosomal genes in monocytic cells elicits distinct paracrine effects on various cardiac cell types. Particularly, silencing of ZFY in macrophages demonstrated profound effects on all investigated cell types, warranting further investigation. Additionally, two long non-coding RNAs, previously unexplored in cardiovascular disease, influenced paracrine activity of macrophages.

Metabolically healthy obesity and cardiovascular outcomes

Abstract Obesity increases cardiovascular risk through a deterioration of the metabolic profile. However, obesity is not always accompanied by a worsening metabolic profile. This longitudinal study aimed to determine whether obesity with a normal metabolic profile, i.e. metabolically healthy obesity, increases the risk of cardiovascular disease. We analyzed a health insurance data of Shizuoka prefecture resident. This data includes data from annual health check-ups performed for insured persons. This study analyzed data from 168,699 individuals aged <65 years. Obesity was defined as ≥ 25 kg/m2 body mass index. Metabolically healthy was defined as ≤ 1 metabolic risk factors (high blood pressure, low high-density lipoprotein cholesterol, high low-density lipoprotein cholesterol, or high hemoglobin A1c). Incidence rate of cardiovascular diseases (stroke and myocardial infarction), and all-cause mortality identified from the insurance data were compared between clinical profile-matched metabolically healthy obesity and non-obesity groups (n = 8,644 each). Clinical parameters, namely systolic blood pressure (standard mean difference = 0.03), HDL cholesterol (0.01), LDL cholesterol (0.01), and hemoglobin A1c (0.01) did not differ among the metabolically healthy obesity and non-obesity groups. The incident rate of stroke (obesity: 9.2 per 10,000 person-years; non-obesity: 10.5; log-rank test P = 0.595), myocardial infarction (obesity: 3.7; non-obesity: 3.1; P = 0.613), and all-cause mortality (obesity: 26.6; nonobesity: 23.2; P = 0.304) also did not differ significantly among the groups even when abdominal obesity was considered in the analysis, though the population with metabolically healthy obesity reported negligibly worse metabolic profiles than the population with nonobese at the 5.6-year follow-up. Obesity, when accompanied by a healthy metabolic profile, did not increase the risk of cardiovascular outcomes and all-cause mortality. Key messages • Metabolically healthy obesity did not increase cardiovascular disease risks. • Metabolically healthy obesity was associated with worse metabolic profiles after a few years later.

Out-of-hospital cardiac arrest in patients with psoriasis

Abstract Background Psoriasis is a complex autoinflammatory disease that has been associated with atherosclerosis, higher risks of cardiovascular diseases, and electrocardiographic changes. Whether these risk factors lead to higher risks of out-of-hospital cardiac arrest (OHCA) is undetermined. Purpose To investigate whether psoriasis is associated with OHCA. Method Using the nationwide Danish Cardiac Arrest Registry, we identified adult (≥18 years) OHCA patients of presumed cardiac cause with and without psoriasis between June 1st 2001 and December 31st 2019. The association of cardiac arrest was estimated using time-varying Cox regression fitted with a nested case-control design where we matched up to five controls per case on age, sex and year of OHCA and 4 comorbidities: ischemic heart disease, congestive heart failure, cardiovascular risk factors, and major extra cardiac organ disease. In subgroup analyses, the main analysis was repeated in patients with severe psoriasis (presence of inpatient hospital contact during the previous year) as compared to mild psoriasis. Results We included 43,967 OHCA cases and matched with 219,772 controls from the general population. The median age was 72 years, 68% were male and 26% had ischemic heart disease, 21% had congestive heart failure, 57% had cardiovascular risk factors, and 33% had extra cardiac organ disease (Table 1). We identified 1,145 (2.6%) cases and 4,971 (2.3%) controls who had psoriasis. Compared with cardiac arrest cases without psoriasis, cases with psoriasis had similar age and sex distribution, prevalence of ischemic heart disease, and congestive heart failure, but a higher prevalence of cardiovascular risk factors, major extra cardiac organ disease and Charlson score distribution. Psoriasis was significantly associated with higher hazard ratios of OHCA: HR 1.16 [95% confidence interval: 1.08 - 1.23] (Figure 1). Compared to no psoriasis, having severe psoriasis was significantly associated with higher hazard of OHCA: HR 1.98 [95% confidence interval: 1.10 - 3.61], while mild psoriasis was not (Figure 1). Conclusion In this nationwide nested case-control study, psoriasis was significantly associated with increased hazard of out-of-hospital cardiac arrest. Furthermore, the association was only significant with severe psoriasis compared to those without psoriasis, while mild psoriasis was not. This study highlights the importance of examining cardiovascular risk factors and prioritizing prevention of cardiovascular disease in patients with psoriasis.Figure 1Table 1

Comorbidity neural network model for personalised recommendations in cardiometabolic risk factor management: towards early precision medicine in routine clinical practice

Abstract Background and Aims Hypertension and hypercholesterolaemia often develop in tandem to confer a risk of cardiovascular disease that may be more than additive. The present study explored early comorbid therapeutic intervention, i.e., beyond individual disease silos, while minimising data bias to provide clinical decision support tools that are portable across clinics. Methods A neural network was created to reproduce UK national clinical guidelines with an accuracy higher than 95%. Relying on real-world evidence from the UK primary care Clinical Practice Research Datalink electronic health record resource, a transfer learning methodology was then applied to achieve recommended risk factor goal attainment after two years. Shapley values derived from game theory were used to define similar digital twin cohorts, and to evaluate individualised recommendations that deviated from national clinical guidelines by rejecting a no-benefit hypothesis retrospectively in a classical proportion test. The methodology was ported to an independent hold-out dataset with anonymized records from six primary care clinics in the South of England. Results The adult patient population (n=469,496, mean+SD age 61+11yr; M 56% vs F 44%; primary 84% vs secondary prevention 16%) included 101,255 diagnosed for hypertension and 112,180 for cholesterol management. While a majority of the 52,504 therapeutic decisions in a test set agree with single morbidity guidelines, for 4639 deviations from the guidance, a significant minority was identified for whom alternative therapy was recommended. Rejecting a no-clinical benefit hypothesis at the 95% confidence level in a retrospective analysis, 1367 decisions showed statistically significant better outcomes over guidelines, for example by escalating anti-hypertensive therapies for patients receiving statin therapy (1085) or by complementing anti-hypertensive therapy with a statin (158). Similar findings were obtained when tested in a hold-out dataset with 13,725 decisions for 6531 patients. Conclusions The results support the contention that machine learning can identify patient subgroups for whom comorbid intervention deviating from clinical guidelines may be appropriate. A novel aspect of the study is the demonstration of clinically portable and actionable application of machine learning in the context of comorbid cardiometabolic diseases. The results represent practical steps towards personalised precision medicine for cardiovascular comorbidity in routine clinical practice.

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.

A direct comparison of non-invasive blood markers of liver fibrosis as associates of cardiovascular risk. The Athens cardiometabolic registry

Abstract Background Non-alcoholic fatty liver disease (NAFLD) is associated with increased risk of cardiovascular disease (CVD). This risk increases further with advanced liver fibrosis. To date, non-invasive tests (NIT) for liver fibrosis risk have not been established as diagnostic or prognostic biomarkers of CVD. Purpose The purpose of the study was to compare NIT of liver fibrosis with respect to their associations with vascular injury and cardiovascular (CV) events. Methods Individuals without clinically overt CVD and patients with CVD (total n=1,692), consecutively recruited in the Athens Cardiometabolic Registry, were analysed in this study. We retrospectively evaluated the association of NIT (i.e. Fibrosis-4 index (FIB-4), NAFLD Fibrosis score (NFS), BARD score) with indices of subclinical arterial injury (i.e. carotid wall thickness and atherosclerotic plaque for subclinical atherosclerosis, pulse wave velocity (PWV), for arterial stiffness) and the incidence of CV events. Patients were followed-up for CV events for a median time of 39 months. Results Elevated FIB-4 (>2.67) was associated with vascular damage [adjusted odds ratio (aOR)=2.97, 95% confidence intervals (CI)= 1.71-5.78 for maximal wall thickness (maxWT) and aOR=4.58, 95% CI=2.44-8.60 for PWV] across the entire study population, including those with or without clinically overt CVD. NFS> 0.675 showed similar associations but lacked significant correlation with arterial stiffness in coronary artery disease patients. FIB-4> 2.67 and BARD> 2 were associated with increased risk of the composite endpoint of CV death, acute myocardial infarction, or coronary revascularization [adjusted hazard ratio, (aHR)=2.00, 95% CI= 1.12-3.55 and aHR=3.36, 95% CI=1.03-11.0 for FIB-4 (n=842) and BARD (n=887) respectively]. FIB-4 and BARD as continuous variables confered incremental prognostic value compared to European Systematic Coronary Risk Evaluation 2 (SCORE2). Conclusion In a population with a wide range of cardiometabolic risk, FIB-4 was associated with both markers of atherosclerotic disease and arterial stiffness as well as with adverse CV events. These data support further investigation of FIB-4 as a biomarker of CV risk.

Association between lipoprotein particle concentration and size and progression of coronary plaque: the MACS Longitudinal Coronary CT angiography study

Abstract Background People living with HIV have greater risk of cardiovascular diseases (CVD) than people without HIV and tend to have different risk profiles, including higher serum triglycerides and lower LDL cholesterol levels. Nuclear magnetic resonance (NMR) provides a detailed phenotype of lipoproteins. Purpose To examine the associations between lipoprotein particle concentrations and size and progression of coronary artery plaque among people living with and without HIV, and whether these associations differ by HIV serostatus. Methods Men with no clinical CVD in the Multicenter AIDS Cohort Study (MACS) who underwent a coronary CT angiography at baseline (2010-13) and follow-up (2015-17) were included. NMR spectroscopy was completed on fasting serum samples at baseline. Logistic regression models for the change in total coronary plaque volume (in tertiles) were estimated with NMR-derived lipoproteins as predictors. Levels were log-transformed and standardized to make results comparable. Models were adjusted for demographics, statin use and HIV serostatus (model 1) with addition of CVD risk factors (model 2). Interactions by HIV serostatus were also tested. Results A total of 549 men (314 with HIV; 235 without HIV) were included. Mean age was 53 ±7 years; 58% were White, 30% Black, and 12% Hispanic. Coronary plaque was present in 70% and plaque volume progressed in 79% of the cohort. Among men with HIV, 81% had undetectable HIV RNA and 12% had a diagnosis of AIDS at baseline. Men with HIV had significantly higher levels of small LDL-P, and total, medium and large VLDL-P levels compared to men without HIV, and lower levels of total, small and large HDL-P (Table 1). Men with HIV had significantly greater progression of plaque volume (37 mm3) compared to men without HIV (31 mm3, p<0.05). Levels of total and small LDL-P concentrations were directly associated with plaque progression, whereas large HDL-P was inversely associated with plaque progression in the combined sample (Model 2). Associations between total and small LDL-P with plaque progression were stronger in men with HIV than in men without HIV in models 1 and 2 (interaction p<0.01). While associations in fully adjusted models for total VLDL-P and small VLDL-P were significant in men without HIV, there were no significant associations between these particle concentrations with coronary plaque progression among men without HIV (interaction p< 0.01) (Model 2, Table 2). Conclusion Associations between lipid particle concentrations and coronary plaque progression differed between men with and without HIV, with stronger associations seen in men without HIV for total and small LDL-P. Despite having higher VLDL and lower HDL particle concentrations at baseline, these particle concentrations were only associated with plaque progression in men without HIV. Further research is needed to elucidate HIV specific factors for plaque progression to tailor risk reduction strategies.

Arrhythmogenic effects of DEHP exposure: insights into cardiac electrophysiology and myocardial cells

Abstract Introduction Hemodialysis patients, who are exposed to plasticizers through the hemodialysis circuit, face a high risk of cardiovascular disease (CVD). Plasticizers, such as the endocrine-disrupting compound Di(2-ethylhexyl) phthalate (DEHP), have emerged as potential contributors to CVD. This study explores the impact of DEHP on cardiac electrophysiology and myocardial cells, providing insights into its cardiotoxic effects. Methods We employed optical mapping techniques to assess cardiac electrophysiology in Langendorff-perfused rat hearts exposed to DEHP, comparing them to a control group. Additionally, we evaluated the effect of DEHP on cardiac muscle cells using H9C2 rat cardiomyoblasts. Results Prolonged DEHP exposure resulted in elevated heart rate, increased electrocardiographic variability, and higher low-frequency values, indicative of sympathetic nervous system overactivity. Action potential duration at APD80 increased, leading to greater action potential triangulation. Electrical alternans observed in the DEHP-treated group heightened the risk of arrhythmias. Single-cell analysis revealed severe mitochondrial damage, myocardial cell apoptosis, and disrupted calcium ion balance. Conclusion This study highlights DEHP's cardiotoxicity, suggesting its potential role in arrhythmogenesis and cardiac dysfunction. Environmental pollutants like DEHP warrant consideration as contributors to cardiovascular diseases, emphasizing the need for further research on preventive strategies.

Serum homocysteine levels and mortality: a cohort study

Abstract Background Homocysteine, an intermediate metabolite derived from dietary methionine, plays a pivotal role in deoxyribonucleic acid expression and contribute to its antioxidant capabilities. Elevated homocysteine levels can increase the risk of cardiovascular disease (CVD), cancer, and neurological disorder; however, low levels of homocysteine are generally not considered harmful. This study evaluates the association between all levels of homocysteine-both low and high-and the risk of all-cause and cause-specific mortality in Korean adult men. Methods A study involving 221,356 Korean adult men categorized them into quintiles based on their homocysteine levels. The main outcomes examined were mortality from all causes, cardiovascular disease (CVD), cancer, and dementia. Hazard ratios (HRs) were determined using Cox proportional hazards models, and the dose-response relationship between homocysteine levels and mortality risk was further analyzed using a restricted cubic splines model. Results Compared to the reference category (Q2, 8.8-9.9 µmol/L), there was a significant increase in all-cause mortality associated with both low and high homocysteine levels after adjusting for multiple variables (Pinteraction=0.002). Furthermore, spline regression revealed a U-shaped relationship between homocysteine levels and both all-cause and CVD mortality, with an inflection point at 9.1 µmol/L. This U-shaped association was not observed in the subgroup that received vitamin supplements. Conclusions Among young and middle-aged Korean adult men, both low and high homocysteine levels were found to increase the risk of all-cause and CVD mortality, demonstrating a U-shaped relationship. However, this association lost statistical significance with vitamin supplementation. These findings underscore the importance of monitoring both low and high homocysteine levels as potential mortality risk factors in men and suggest a possible protective role of vitamins. Key messages • Both low and high levels of homocysteine in young and middle-aged Korean men are associated with increased risks of all-cause and cardiovascular mortality, demonstrating a U-shaped relationship. • Vitamin supplementation appears to nullify this association, suggesting a potential protective effect against mortality.