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Background In England, as for many countries, there are geographical variations in treatment uptake and outcomes for patients with early breast cancer (EBC). It is important such inequalities are addressed. The co-existence of cardiovascular disease (CVD) in patients with early breast cancer (EBC) may complicate treatment choices, lead to deviations from standard of care, and be associated with worse cancer and CVD outcomes. Social deprivation is also associated with increased incidence of co-morbidities, reduced cancer treatment rates, and worse cancer survival. If there are regional differences in rates of CVD/co-morbidities and social deprivation these may explain observed differences in treatment uptake and cancer outcomes in EBC. Therefore, in this analysis we evaluated rates of CVD and social deprivation in a large population of patients with EBC in 20 English Cancer Alliances. Methods Cancer registry data as part of The Virtual Cardio-Oncology Research Initiative (VICORI) were used to identify patients diagnosed with stage I-III breast cancer diagnosed between 2013 - 2018 in England. National data (hospital records and national cardiovascular audit databases) were used to describe CVD prevalence (CVDp), Index of Multiple Deprivation (IMD), and Charlson Comorbidity Index (CCI). Patient, disease, tumour, and treatment characteristics were allocated into Cancer Alliance tertiles according to CVDp (minimum (< 33.3rd percentile); middle (33.3rd – 66.6th percentile); maximum (>66.6th percentile)) with approximately equal patient numbers in each group. The disease burden was depicted in bar charts and regional variation as heat maps of England. The percentage of patients in the most deprived quintile of income domain of the IMD were plotted. Funnel plots were used to investigate variations in regional CVD rates based on a logistic regression model. Results Data from 226,516 patients with stage I-IIIA breast cancer with a mean age of 62.5 (+/- 13.7) were included in the analysis. 78,833 patients were assigned to the minimum (37.0%; 95% CI 36.7 – 37.2), 74,443 to the middle (35.5%; 95% CI 35.3 – 35.7), and 73,240 to the maximum (34.7%; 95% CI 34.5 – 34.9) tertile. Geographical variation between Cancer Alliances was demonstrated for CVDp (6% - 9.5%), IMD (2%- 30%), and CCI  4 (8.2% - 9.5%). Variation of CVDp revealed a South/North gradient between Cancer Alliances towards higher percentage, with centrifugal tendency from London. These findings were consistent with a similar pattern seen for variation in IMD quintiles with higher prevalence of most socioeconomic deprived patients located in cancer alliances in the North compared to the South of England. Regional variation was less obvious for CCI. After adjusting for age, TNM stage, IMD, and CCI, differences in the standardised CVD ratio persisted for some cancer alliances suggesting that other factors than those adjusted for are likely accountable for the higher CVDp seen in some Cancer Alliances. An adjusted ordinal logistic regression model demonstrated that older age (aged >75), white ethnicity, and social deprivation were associated with a higher risk of CVDp (p< 0.001). Conclusions This study highlights significant geographical variation of social deprivation, CVDp, and other comorbidities in early breast cancer patients in England which may contribute to the variability in treatment received and breast cancer survival in different regions within the country. Citation Format: Jasmin V Waterhouse, Catherine A. Welch, Nicolo M.L. Battisti, David Adlam, Michael J. Sweeting, Lizz Paley, Paul Lambert, John E. Deanfield, Mark de Belder, Michael D Peake, Alistair Ring. Geographical variation of social deprivation, cardiovascular and other comorbidities in 226,516 patients with early breast cancer in England: results from a National Registry Dataset Analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-08-04.

Evaluate the effects of once-weekly subcutaneous semaglutide 2.4 mg on cardiometabolic risk factors in people with overweight/obesity without diabetes in the STEP 1 and 4 trials.STEP 1 and 4 were phase III, 68-week, placebo-controlled trials of once-weekly semaglutide 2.4 mg combined with lifestyle intervention; STEP 4 had a 20-week semaglutide run-in and 48-week randomized withdrawal period. Participants had a body mass index ≥30 kg/mOf the 1961 participants in STEP 1 and 803 in STEP 4, most had one or more complication/comorbidity at baseline, with dyslipidaemia and hypertension most prevalent. In STEP 1, reductions in waist circumference, SBP, DBP, FPG, fasting serum insulin, lipids and HOMA-IR were greater with semaglutide versus placebo (p ≤ .001). Reductions in SBP, non-HDL cholesterol, low-density lipoprotein cholesterol and FPG were generally greater with semaglutide than placebo within weight-loss categories. Non-significant ASCVD risk reductions were observed with semaglutide versus placebo (p .05). In STEP 4, improvements in waist circumference, SBP, FPG, fasting serum insulin and lipids during the semaglutide run-in (week 0-20) were maintained over week 20-68 with continued semaglutide, but deteriorated following the switch to placebo (p .001 [week 20-68]). Net reductions in antihypertensive/lipid-lowering medication use occurred with semaglutide versus placebo (both trials).Semaglutide may improve cardiometabolic risk factors and reduce antihypertensive/lipid-lowering medication use versus placebo in adults with overweight/obesity without diabetes. These potential benefits were not maintained after treatment discontinuation.STEP 1 NCT03548935, STEP 4 NCT03548987.

Aims The effect of the COVID-19 pandemic on care and outcomes across non-COVID-19 cardiovascular (CV) diseases is unknown. A systematic review and meta-analysis was performed to quantify the effect and investigate for variation by CV disease, geographic region, country income classification and the time course of the pandemic. Methods and results From January 2019 to December 2021, Medline and Embase databases were searched for observational studies comparing a pandemic and pre-pandemic period with relation to CV disease hospitalisations, diagnostic and interventional procedures, outpatient consultations, and mortality. Observational data were synthesised by incidence rate ratios (IRR) and risk ratios (RR) for binary outcomes and weighted mean differences for continuous outcomes with 95% confidence intervals. The study was registered with PROSPERO (CRD42021265930). A total of 158 studies, covering 49 countries and 6 continents, were used for quantitative synthesis. Most studies (80%) reported information for high-income countries (HICs). Across all CV disease and geographies there were fewer hospitalisations, diagnostic and interventional procedures, and outpatient consultations during the pandemic. By meta-regression, in low-middle income countries (LMICs) compared to HICs the decline in ST-segment elevation myocardial infarction (STEMI) hospitalisations (RR 0.79, 95% confidence interval [CI] 0.66–0.94) and revascularisation (RR 0.73, 95% CI 0.62–0.87) was more severe. In LMICs, but not HICs, in-hospital mortality increased for STEMI (RR 1.22, 95% CI 1.10–1.37) and heart failure (RR 1.08, 95% CI 1.04–1.12). The magnitude of decline in hospitalisations for CV diseases did not differ between the first and second wave. Conclusions There was substantial global collateral CV damage during the COVID-19 pandemic with disparity in severity by country income classification.

Identifying genetic determinants for longitudinal changes in albumin excretion in individuals with type 1 diabetes may help identify those that are predisposed to renal, retinal and cardiovascular complications. Most studies have focussed on genetic predisposition to diabetic kidney disease and used cross-sectional measurements of urinary albumin excretion, but with limited success. Here, we utilise the wealth of longitudinal data and bio-samples collected from cohorts of childhood-onset type 1 diabetes followed over the last 30 years to describe a novel trajectory phenotype quantifying urinary albumin excretion changes during childhood and adolescence. We conducted a genome-wide association study and fine-mapping analysis for albumin excretion in 1584 individuals, finding one signal for cross-sectional albumin excretion close toGALNTL6(rs150766792), which validated in a previous independent study, and a novel genome-wide significant signal for albumin excretion trajectory in theCDH18gene region (rs145715205). Our trajectory phenotype quantifies albumin progression and offers a complementary measure to an albumin excretion phenotype based on a single measurement (i.e. most recent data collection) or an average of repeated measurements in longitudinal studies. It can be used to identify genetic or other risk factors which predict better or worse prognosis, thus facilitating the development of new preventive and therapeutic approaches.

Background \ud There is variability in the impact of adult congenital heart disease (ACHD) on health-related quality of life (HRQoL). A greater insight into the impact of ACHD may be gained from investigating HRQoL in various diagnostic groups and considering the importance of psychosocial risk factors for poor HRQoL.\ud \ud Objective \ud We compared the HRQoL of people with ACHD with normative data from the general population and among 4 diagnostic groups and identified risk factors for poor HRQoL in ACHD from a comprehensive set of sociodemographic, clinical, and psychosocial factors.\ud \ud Methods \ud We conducted a cross-sectional study with 303 participants from 4 diagnostic groups Simple, Tetralogy of Fallot, Transposition of the Great Arteries, Single Ventricle who completed measures of illness perceptions, coping, social support, mood, and generic and disease-specific HRQoL. Data were analyzed using 1-sample t tests, analysis of variance, and hierarchical multiple regressions.\ud \ud Results \ud There was diminished psychosocial HRQoL in the Simple group compared with the general population. Consistently significant risk factors for poor HRQoL included younger age, a perception of more severe symptoms due to ACHD, depression, and anxiety. Clinical factors were poor predictors of HRQoL.\ud \ud Conclusions \ud The findings highlight the need to develop intervention studies aiming to improve HRQoL in people with ACHD and the routine assessment of illness perceptions and mood problems during key periods in people's lives. This will help address patient misconceptions that could be tackled by clinicians or specialist nurses during routine outpatient appointments and identify people in need of psychological support.

Inflammation is a key driver of atherosclerotic cardiovascular disease. C-reactive protein (CRP), an established biomarker of inflammation, is commonly elevated in people with overweight/obesity.STEP 1, 2, and 3 were 68-week, placebo-controlled trials of semaglutide for weight management in participants with overweight/obesity, with (STEP 2) or without (STEP 1 and 3) type 2 diabetes. Change in serum CRP from baseline to week 68 was assessed as a prespecified secondary endpoint for semaglutide 2.4 mg versus placebo (STEP 1, 2, and 3) and versus semaglutide 1.0 mg (STEP 2).The trials took place from June through November 2018 (STEP 1 and 2) and from August 2018 to April 2020 (STEP 3). In all trials, semaglutide 2.4 mg reduced CRP at week 68 versus placebo (estimated treatment difference [ETD; 95% CI] -44% [-49 to -39] in STEP 1, -39% [-46 to -30] in STEP 2, and -48% [-55 to -39] in STEP 3; all p 0.05). In STEP 2, CRP reductions were greater with semaglutide 2.4 mg (-49%) than with 1.0 mg (-42%) but the difference did not reach statistical significance (ETD [95% CI] -12% [-23 to 1]; p = 0.06). Reductions in CRP occurred in parallel with bodyweight loss and were consistent regardless of baseline BMI/bodyweight/glycaemic status. More semaglutide-treated participants had reductions in CRP-defined cardiovascular risk versus those on placebo. Reductions in CRP were positively correlated with reductions in bodyweight, waist circumference, fasting plasma glucose, fasting serum insulin, and HOMA-IR (data not shown).In people with overweight/obesity, once-weekly semaglutide 2.4 mg and 1.0 mg reduced CRP concentration irrespective of baseline BMI/bodyweight/glycaemic status compared with placebo. These data suggest a potential anti-inflammatory role of semaglutide in obesity.Novo Nordisk.

This manuscript is a personal tribute to Professor Marc de Leval from two of his colleagues: Professor Martin J. Elliott and Professor John E. Deanfield. As stated by the authors: “Marc’s career history is presented in the accompanying eulogy from the current Heart & Lung Team at Great Ormond Street Hospital (GOSH), allowing us to highlight Marc’s personal qualities that made him such an inspirational colleague. … Marc was, as we have said, the cardiologist’s surgeon. He was also the surgeon’s cardiologist, bridging the two disciplines and fusing the team. He was delighted by the advent of interventional cardiology and did not see it as a threat or competition, but instead, as appropriate for the well-being of his patients. He recognised how traumatic surgery could be for patients and their families and sought to avoid it whenever possible by alternative treatments. Marc will be remembered with love and admiration by his many patients and their families, whose lives he changed. His technical skill, energy, devotion, humour, intellect and influence will be sorely missed. May he rest in peace.”

For many years, clinical studies could not show that lowering glucose in patients with type 2 diabetes leads to better macrovascular outcomes. In the past few years, new data have shown that treatment with two classes of dugs developed as "glucose-lowering agents," SGLT2 inhibitors and GLP-1 receptor agonists, can reduce macrovascular and renal complications. These studies have prompted debate about the main aim of type 2 diabetes management. In this review, three eras of diabetes management are described according to the treatment recommendations, such as the ADA/EASD consensus, moving from a pure glucocentric view into the present cardio-renal outcome-oriented approach, this has been endorsed by major diabetes and cardiology societies. While in the first era normalizing HbA1c was the only focus (e.g., UK Prospective Diabetes Study), failing to show a reduction in cardiovascular morbidity and mortality, further studies analyzing the pros and cons of intensified control such as ACCORD, VADT, ADVANCE recognized that treatment intensification was associated with weight gain and hypoglycemia, thereby potentially reducing the benefits of glycemic control. Therefore, the focus in the second area was on controlling HbA1c without these unwanted effects. The consistent beneficial results of several cardiovascular outcome trials with SGLT2 inhibitors and GLP-1 receptor agonists showing significantly improved cardio-renal outcomes, induced a paradigm shift: a change from (only) control of HbA1c to an organ-protective approach with the main focus now on cardio-renal risk; this is now considered as the third era. Recent data indicating beneficial effects of glucose-lowering agents in particular SGLT2 inhibitors even in subjects without diabetes, improving hospitalization for heart failure and renal outcomes might reveal another new era, which could then be considered a fourth era. While current international guidelines call for this paradigm shift, registry data show that we are still far from translating this objective into real-world practice.

Supplemental Digital Content is available in the text., Increases in aortic pulse wave velocity, a measure of arterial stiffness, can lead to elevated systolic blood pressure and increased cardiac afterload in adulthood. These changes are detectable in childhood and potentially originate in utero, where an adverse early life environment can alter DNA methylation patterns detectable at birth. Here, analysis of epigenome-wide methylation patterns using umbilical cord blood DNA from 470 participants in the Southampton’s Women’s Survey identified differential methylation patterns associated with systolic blood pressure, pulse pressure, arterial distensibility, and descending aorta pulse wave velocity measured by magnetic resonance imaging at 8 to 9 years. Perinatal methylation levels at 16 CpG loci were associated with descending aorta pulse wave velocity, with identified CpG sites enriched in pathways involved in DNA repair (P=9.03×10−11). The most significant association was with cg20793626 methylation (within protein phosphatase, Mg2+/Mn2+ dependent 1D; β=−0.05 m/s/1% methylation change, [95% CI, −0.09 to −0.02]). Genetic variation was also examined but had a minor influence on these observations. Eight pulse wave velocity-linked dmCpGs were associated with prenatal modifiable risk factors, with cg08509237 methylation (within palmitoyl-protein thioesterase-2) associated with maternal oily fish consumption in early and late pregnancy. Lower oily fish consumption in early pregnancy modified the relationship between methylation and pulse wave velocity, with lower consumption strengthening the association between cg08509237 methylation and increased pulse wave velocity. In conclusion, measurement of perinatal DNA methylation signatures has utility in identifying infants who might benefit from preventive interventions to reduce risk of later cardiovascular disease, and modifiable maternal factors can reduce this risk in the child.

Aims To assess the recording and accuracy of acute myocardial infarction (AMI) hospital admissions between two electronic health record databases within an English cancer population over time and understand the factors that affect case-ascertainment. Methods and results We identified 112 502 hospital admissions for AMI in England 2010–2017 from the Myocardial Ischaemia National Audit Project (MINAP) disease registry and hospital episode statistics (HES) for 95 509 patients with a previous cancer diagnosis up to 15 years prior to admission. Cancer diagnoses were identified from the National Cancer Registration Dataset (NCRD). We calculated the percentage of AMI admissions captured by each source and examined patient characteristics associated with source of ascertainment. Survival analysis assessed whether differences in survival between case-ascertainment sources could be explained by patient characteristics. A total of 57 265 (50.9%) AMI admissions in patients with a prior diagnosis of cancer were captured in both MINAP and HES. Patients captured in both sources were younger, more likely to have ST-segment elevation myocardial infarction and had better prognosis, with lower mortality rates up to 9 years after AMI admission compared with patients captured in only one source. The percentage of admissions captured in both data sources improved over time. Cancer characteristics (site, stage, and grade) had little effect on how AMI was captured. Conclusion MINAP and HES define different populations of patients with AMI. However, cancer characteristics do not substantially impact on case-ascertainment. These findings support a strategy of using multiple linked data sources for observational cardio-oncological research into AMI.

BackgroundThe COVID-19 pandemic has resulted in a high death toll. We aimed to describe the place and cause of death during the COVID-19 pandemic.MethodsThis national death registry included all adult (aged ≥18 years) deaths in England and Wales between 1st January 2014 and 30th June 2020. Analyses were based upon ICD-10 codes corresponding to the underlying cause of death as stated on the Medical Certificate of Cause of Death. Daily deaths during COVID-19 pandemic were compared against the expected daily deaths estimated using Farrington surveillance algorithm for daily historical data between 2014 and 2020, by place and cause of death.FindingsBetween 2nd March and 30th June 2020, there was an excess mortality of 57,860 (a proportional increase of 35%) compared with the expected deaths, of which 50,603 (86.2%) were COVID-19 related. Almost half the excess deaths occurred in care homes (25,611 deaths) where deaths were 55% higher than expected. One fifth of the excess deaths occurred in hospital (15,938 deaths; a proportional increase of 21%) with the remainder occurring at home (16,190 deaths; a proportional increase of 39%). At home, only 14% of 16,190 excess deaths were related to COVID-19, with 5,963 deaths due to cancer and 2,485 deaths due to cardiac disease, very few of which involved COVID-19. In care homes or hospices, 61% of the 25,611 excess deaths were related to COVID-19, 5,539 of which were due to respiratory disease and most of these (4,315 deaths) involved COVID-19. In hospital, there were 16,174 fewer deaths than expected which did not involve COVID-19, and there were 4,088 fewer deaths due to cancer and 1,398 fewer deaths due to cardiac disease than expected.InterpretationThe COVID-19 pandemic has resulted in a substantial increase in the absolute numbers of deaths occurring at home and care homes. There was a huge burden of excess deaths occurring in care homes, which were poorly characterised, and were likely to be, at least in part, the result of undiagnosed COVID-19. There was a smaller but important and ongoing excess in deaths at home, particularly from cancer and cardiac disease, which suggests avoidance of hospital care for non-COVID-19 conditions.FundingThe study is unfunded.

Objectives This study characterized the determinants of carotid intima-media thickness (cIMT) in a large (n > 4,000) longitudinal cohort of healthy young people age 9 to 21 years. Background Greater cIMT is commonly used in the young as a marker of subclinical atherosclerosis, but its evolution at this age is still poorly understood. Methods Associations between cardiovascular risk factors and cIMT were investigated in both longitudinal (ages 9 to 17 years) and cross-sectional (ages 17 and 21 years) analyses, with the latter also related to other measures of carotid structure and stress. Additional use of ultra-high frequency ultrasound in the radial artery at age 21 years allowed investigation of the distinct layers (i.e., intima or media) that may underlie observed differences. Results Fat-free mass (FFM) and systolic blood pressure were the only modifiable risk factors positively associated with cIMT (e.g., mean difference in cIMT per 1-SD increase in FFM at age 17: 0.007 mm: 95% confidence interval [CI]: 0.004 to 0.010; p Conclusions Subtle changes in cIMT in the young may predominantly involve the media and represent physiological adaptations as opposed to subclinical atherosclerosis. Other vascular measures might be more appropriate for the identification of arterial disease before adulthood.

An increased albumin-creatinine ratio within the normal range can identify adolescents at higher risk of developing adverse cardio-renal outcomes as they progress into adulthood. Utilizing a parallel randomized controlled trial and observational cohort study, we characterized the progression of vascular phenotypes throughout this important period and investigated the effect of ACE (angiotensin-converting enzyme) inhibitors and statins in high-risk adolescents. Endothelial function (flow-mediated dilation and reactive hyperemia index) and arterial stiffness (carotid-femoral pulse wave velocity) were assessed in 158 high-risk participants recruited to a randomized, double-blind placebo-controlled 2×2 factorial trial (randomized, placebo-controlled trial) of ACE inhibitors and/or statins in adolescents with type 1 diabetes (AdDIT [Adolescent Type 1 Diabetes cardio-renal Intervention Trial]). Identical measures were also assessed in 215 lower-risk individuals recruited to a parallel observational study. In the randomized, placebo-controlled trial, high-risk patients randomized to ACE inhibitors had improved flow-mediated dilation after 2 to 4 years of follow-up (mean [95% CI]: 6.6% [6.0–7.2] versus 5.3% [4.7–5.9]; P =0.005), whereas no effect was observed following statin use (6.2% [5.5–6.8] versus 5.8% [5.1–6.4]; P =0.358). In the observational study, patients classed as high-risk based on albumin-creatinine ratio showed evidence of endothelial dysfunction at the end of follow-up (flow-mediated dilation=4.8% [3.8–5.9] versus 6.3% [5.8–6.7] for high-risk versus low-risk groups; P =0.015). Neither reactive hyperemia index nor pulse wave velocity were affected by either treatment ( P >0.05 for both), but both were found to increase over the duration of follow-up (0.07 [0.03–0.12]; P =0.001 and 0.5 m/s [0.4–0.6]; P Registration— URL: https://www.clinicaltrials.gov ; Unique identifier NCT01581476.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality. Although it has been widely appreciated that obesity is a major risk factor for CVD, treatments that produce effective, durable weight loss and the impact of weight reduction in reducing cardiovascular risk have been elusive. Instead, progress in CVD risk reduction has been achieved through medications indicated for controlling lipids, hyperglycemia, blood pressure, heart failure, inflammation, and/or thrombosis. Obesity has been implicated as promoting all these issues, suggesting that sustained, effective weight loss may have independent cardiovascular benefit. GLP-1 receptor agonists (RAs) reduce weight, improve glycemia, decrease cardiovascular events in those with diabetes, and may have additional cardioprotective effects. The GLP-1 RA semaglutide is in phase 3 studies as a medication for obesity treatment at a dose of 2.4 mg subcutaneously (s.c.) once weekly. Semaglutide Effects on Heart Disease and Stroke in Patients with Overweight or Obesity (SELECT) is a randomized, double-blind, parallel-group trial testing if semaglutide 2.4 mg subcutaneously once weekly is superior to placebo when added to standard of care for preventing major adverse cardiovascular events in patients with established CVD and overweight or obesity but without diabetes. SELECT is the first cardiovascular outcomes trial to evaluate superiority in major adverse cardiovascular events reduction for an antiobesity medication in such a population. As such, SELECT has the potential for advancing new approaches to CVD risk reduction while targeting obesity.

OBJECTIVES: To identify biomarkers of renal disease in adolescents with type 1 diabetes (T1D) and to compare findings in adults with T1D.METHODS: Twenty-five serum biomarkers were measured, using a Luminex platform, in 553 adolescents (median [interquartile range] age: 13.9 [12.6, 15.2] years), recruited to the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial. Associations with baseline and final estimated glomerular filtration rate (eGFR), rapid decliner and rapid increaser phenotypes (eGFR slopes 3 mL/min/1.73m2 /year, respectively), and albumin-creatinine ratio (ACR) were assessed. Results were also compared with those obtained in 859 adults (age: 55.5 [46.1, 64.4) years) from the Scottish Diabetes Research Network Type 1 Bioresource.RESULTS: In the adolescent cohort, baseline eGFR was negatively associated with trefoil factor-3, cystatin C, and beta-2 microglobulin (B2M) (B coefficient[95%CI]: -0.19 [-0.27, -0.12], P = 7.0 × 10-7 ; -0.18 [-0.26, -0.11], P = 5.1 × 10-6 ; -0.12 [-0.20, -0.05], P = 1.6 × 10-3 ), in addition to clinical covariates. Final eGFR was negatively associated with osteopontin (-0.21 [-0.28, -0.14], P = 2.3 × 10-8 ) and cystatin C (-0.16 [-0.22, -0.09], P = 1.6 × 10-6 ). Rapid decliner phenotype was associated with osteopontin (OR: 1.83 [1.42, 2.41], P = 7.3 × 10-6 ), whereas rapid increaser phenotype was associated with fibroblast growth factor-23 (FGF-23) (1.59 [1.23, 2.04], P = 2.6 × 10-4 ). ACR was not associated with any of the biomarkers. In the adult cohort similar associations with eGFR were found; however, several additional biomarkers were associated with eGFR and ACR.CONCLUSIONS: In this young population with T1D and high rates of hyperfiltration, osteopontin was the most consistent biomarker associated with prospective changes in eGFR. FGF-23 was associated with eGFR increases, whereas trefoil factor-3, cystatin C, and B2M were associated with baseline eGFR.

Visual Abstract, Highlights • Combining CHD phenotype–driven gene set enrichment and CRISPR knockdown screening in zebrafish is an effective approach to identifying novel CHD genes. • Mutations affecting genes coding for the WAVE2 protein complex and small GTPase-mediated signaling are associated with LVOTO lesions. • WAVE2 complex genes brk1, nckap1, and wasf2 and regulators of small GTPase signaling cul3a and racgap1 are critical to zebrafish heart development., Summary Genetic variants are the primary driver of congenital heart disease (CHD) pathogenesis. However, our ability to identify causative variants is limited. To identify causal CHD genes that are associated with specific molecular functions, the study used prior knowledge to filter de novo variants from 2,881 probands with sporadic severe CHD. This approach enabled the authors to identify an association between left ventricular outflow tract obstruction lesions and genes associated with the WAVE2 complex and regulation of small GTPase-mediated signal transduction. Using CRISPR zebrafish knockdowns, the study confirmed that WAVE2 complex proteins brk1, nckap1, and wasf2 and the regulators of small GTPase signaling cul3a and racgap1 are critical to cardiac development.

The factors that influence survival during severe infection are unclear. Extracellular chromatin drives pathology, but the mechanisms enabling its accumulation remain elusive. Here, we show that in murine sepsis models, splenocyte death interferes with chromatin clearance through the release of the DNase I inhibitor actin. Actin-mediated inhibition was compensated by upregulation of DNase I or the actin scavenger gelsolin. Splenocyte death and neutrophil extracellular trap (NET) clearance deficiencies were prevalent in individuals with severe COVID-19 pneumonia or microbial sepsis. Activity tracing by plasma proteomic profiling uncovered an association between low NET clearance and increased COVID-19 pathology and mortality. Low NET clearance activity with comparable proteome associations was prevalent in healthy donors with low-grade inflammation, implicating defective chromatin clearance in the development of cardiovascular disease and linking COVID-19 susceptibility to pre-existing conditions. Hence, the combination of aberrant chromatin release with defects in protective clearance mechanisms lead to poor survival outcomes.

SummaryHyperinflammation, coagulopathy and immune dysfunction are prominent in patients with severe infections. Extracellular chromatin clearance by plasma DNases suppresses such pathologies in mice but whether severe infection interferes with these pathways is unclear. Here, we show that patients with severe SARS-CoV-2 infection or microbial sepsis exhibit low extracellular DNA clearance capacity associated with the release of the DNase inhibitor actin. Unlike naked DNA degradation (DNase), neutrophil extracellular trap degradation (NETase) was insensitive to G-actin, indicating distinct underlying mechanisms. Activity-based proteomic profiling of severely ill SARS-CoV-2 patient plasma revealed that patients with high NETase and DNase activities exhibited 18-fold higher survival compared to patients with low activity proteomic profiles. Remarkably, low DNA clearance capacity was also prominent in healthy individuals with chronic inflammation, suggesting that pre-existing inflammatory conditions may increase the risk for mortality upon infection. Hence, functional proteomic profiling illustrates that non-redundant DNA clearance activities protect critically ill patients from mortality, uncovering protein combinations that can accurately predict mortality in critically ill patients.

BACKGROUND AND AIMS: Perinatal HIV infection (PHIV) and prolonged use of antiretroviral therapy (ART) may increase the likelihood of developing subclinical vascular dysfunction at an early age. We conducted a systematic review to assess the effect of PHIV and ART on intima-media thickness (IMT), arterial stiffness and endothelial function in individuals aged 6-25 years. METHODS: Medline, Embase and Web of Science were searched, and studies screened by two independent reviewers. We performed a meta-analysis on selected studies reporting on IMT. RESULTS: A total of 680 studies were retrieved from the databases, with 21 studies deemed eligible for qualitative analysis. There were few studies assessing IMT, arterial stiffness and endothelial function. More than half of the studies found either increased IMT, stiffer arteries or impaired endothelial function in PHIV compared to uninfected controls. A minority of the studies reported that the two groups had similar vascular parameters, a conflicting finding. There was a lack of standardisation for IMT assessment and reporting in numerous studies. In a meta-analysis of seven studies with matching methodologies, IMT was higher in PHIV compared to uninfected controls, (mean difference, 0.05 (0.01-0.09; p = 0.01) but heterogeneity between the studies was substantial (I2, 96.7%; p

Cardiovascular risk is determined by many factors including genetics predisposition, environmental factors, and lifestyle. These need to be considered when evaluating risk of future cardiovascular events in an individual patient. The important modifiable risk factors are diabetes, cholesterol, smoking and blood pressure which together with family history and lifestyle influences (stress, obesity, alcohol, physical activity) account for more than 90% of heart attacks and strokes. The ScoreCard of the European Society of Cardiology can be used now to determine the 10-year risk of a major cardiovascular event, such as myocardial infarction, stroke, and cardiovascular death and this can be used as a guide to choice of treatment. Other important factors, such as noise, pollution, socio-economic status will influence cardiovascular risk, but are difficult to incorporate when managing an individual patient.

Background Smoking tobacco and drinking alcohol are associated with increased arterial stiffness, a critical intermediate endpoint for cardiovascular disease, in adults and in teenagers. The relationship between these risky behaviours and changes in arterial stiffness from late adolescence to early adulthood is not known. Purpose To investigate associations between smoking and drinking habits and the change in arterial stiffness between ages 17 and 24 using a large population-based cohort. Methods Participants underwent repeated measurements of arterial stiffness (carotid-femoral pulse wave velocity (cfPWV)), anthropometrics, resting blood pressure and blood biomarkers, at ages 17 and 24 years. Participants were grouped and scored by alcohol (never, medium intensity (MI): ≤4 drinks on a typical day of drinking, high intensity (HI): >5) and smoking (never, past, MI, Results 1,655 participants (1,013 females and 642 males) had cfPWV recorded at both ages. cfPWV increased from 17 to 24 years in both women (ΔPWV 0.56m/s (0.50, 0.62), p Conclusion Smoking and alcohol use in young adulthood is associated with an accelerated increase in arterial stiffness, with evidence of a graded adverse association for alcohol. Our findings also suggest that adverse effects of smoking in youth may be reversible with smoking cessation. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation

AimsCoronary computed tomography angiography (CCTA) is a first-line modality in the investigation of suspected coronary artery disease (CAD). Mapping of perivascular fat attenuation index (FAI) on routine CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which integrates standardized FAI mapping together with clinical risk factors and plaque metrics to provide individualized cardiovascular risk prediction.Methods and resultsThe study included 3912 consecutive patients undergoing CCTA as part of clinical care in the USA (n = 2040) and Europe (n = 1872). These cohorts were used to generate age-specific nomograms and percentile curves as reference maps for the standardized interpretation of FAI. The first output of CaRi-Heart® is the FAI-Score of each coronary artery, which provides a measure of coronary inflammation adjusted for technical, biological, and anatomical characteristics. FAI-Score is then incorporated into a risk prediction algorithm together with clinical risk factors and CCTA-derived coronary plaque metrics to generate the CaRi-Heart® Risk that predicts the likelihood of a fatal cardiac event at 8 years. CaRi-Heart® Risk was trained in the US population and its performance was validated externally in the European population. It improved risk discrimination over a clinical risk factor-based model [Δ(C-statistic) of 0.085, P = 0.01 in the US Cohort and 0.149, P < 0.001 in the European cohort] and had a consistent net clinical benefit on decision curve analysis above a baseline traditional risk factor-based model across the spectrum of cardiac risk.ConclusionMapping of perivascular FAI on CCTA enables the non-invasive detection of coronary artery inflammation by quantifying spatial changes in perivascular fat composition. We now report the performance of a new medical device, CaRi-Heart®, which allows standardized measurement of coronary inflammation by calculating the FAI-Score of each coronary artery. The CaRi-Heart® device provides a reliable prediction of the patient's absolute risk for a fatal cardiac event by incorporating traditional cardiovascular risk factors along with comprehensive CCTA coronary plaque and perivascular adipose tissue phenotyping. This integration advances the prognostic utility of CCTA for individual patients and paves the way for its use as a dual diagnostic and prognostic tool among patients referred for CCTA.

Objective: Inflammation, oxidative stress, and endothelial dysfunction are known to contribute to ischemia-reperfusion injury. Remote ischemic preconditioning (RIPC) protects from endothelial dysfunction and the damage induced by ischemia-reperfusion. Using intensive periodontal treatment (IPT), an established human model of acute systemic inflammation, we investigated whether RIPC prevents endothelial dysfunction and modulates systemic levels of inflammation and oxidative stress. Approach and Results: Forty-nine participants with periodontitis were randomly allocated to receive either 3 cycles of ischemia-reperfusion on the upper limb (N=24, RIPC) or a sham procedure (N=25, control) before IPT. Endothelial function assessed by flow-mediated dilatation of the brachial artery, inflammatory cytokines, markers of vascular injury, and oxidative stress were evaluated at baseline, day 1, and day 7 after IPT. Twenty-four hours post-IPT, the RIPC group had lower levels of IL-10 (interleukin-10) and IL-12 (interleukin-12) compared with the control group ( P P for interaction P for interaction P =0.011). After 7 days from IPT, most of the inflammatory markers, endothelial-dependent and -independent vasodilation, were similar between groups. Conclusions: RIPC prevented acute endothelial dysfunction by modulation of inflammation and oxidation processes in patients with periodontitis following exposure to an acute inflammatory stimulus. Registration: URL: https://clinicaltrials.gov/ct2/show/NCT03072342 ; Unique identifier: NCT03072342.

BACKGROUND: Patients with underlying cardiovascular disease and coronavirus disease 2019 (COVID‐19) infection are at increased risk of morbidity and mortality. OBJECTIVES: This study was designed to characterize the presenting profile and outcomes of patients hospitalized with acute coronary syndrome (ACS) and COVID‐19 infection. METHODS: This observational cohort study was conducted using multisource data from all acute NHS hospitals in England. All consecutive patients hospitalized with diagnosis of ACS with or without COVID‐19 infection between 1 March and 31 May 2020 were included. The primary outcome was in‐hospital and 30‐day mortality. RESULTS: A total of 12 958 patients were hospitalized with ACS during the study period, of which 517 (4.0%) were COVID‐19‐positive and were more likely to present with non‐ST‐elevation acute myocardial infarction. The COVID‐19 ACS group were generally older, Black Asian and Minority ethnicity, more comorbid and had unfavourable presenting clinical characteristics such as elevated cardiac troponin, pulmonary oedema, cardiogenic shock and poor left ventricular systolic function compared with the non‐COVID‐19 ACS group. They were less likely to receive an invasive coronary angiography (67.7% vs 81.0%), percutaneous coronary intervention (PCI) (30.2% vs 53.9%) and dual antiplatelet medication (76.3% vs 88.0%). After adjusting for all the baseline differences, patients with COVID‐19 ACS had higher in‐hospital (adjusted odds ratio (aOR): 3.27; 95% confidence interval (CI): 2.41–4.42) and 30‐day mortality (aOR: 6.53; 95% CI: 5.1–8.36) compared to patients with the non‐COVID‐19 ACS. CONCLUSION: COVID‐19 infection was present in 4% of patients hospitalized with an ACS in England and is associated with lower rates of guideline‐recommended treatment and significant mortality hazard.

Background Evidence suggests that adverse outcomes in COVID-19 may be driven by a cytokine-induced vascular inflammatory response, caused by SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). Aim We aimed to develop a non-invasive method for quantifying cytokine-driven vascular inflammation in patients with acute COVID-19 infection that could allow risk stratification. Methods We developed a platform for rapid development of novel imaging biomarkers of vascular inflammation, by applying quantitative radiotranscriptomics to images from standard Computed Tomography Angiography (CTA). We used this platform to train a radiotranscriptomic signature (C19-RS) from the perivascular space around the aorta and the internal mammary artery, visualized in routine chest CTAs, to best describe cytokine-driven vascular inflammation, defined using transcriptomic profiles from RNA sequencing data from human arterial biopsies. This signature was tested externally in 435 clinically indicated CT pulmonary angiograms (CTPAs) from patients with or without COVID-19 from 3 different geographical regions. Results COVID-19 patients were characterised by significantly higher C19-RS values (adjusted odds ratio of 2.97 [95%CI: 1.43–6.27], p=0.004), while patients infected with the new B.1.1.7 variant (“UK variant”) were also found to have higher C19-RS values compared to those with the original variant, evidence suggestive of higher degrees of vascular inflammation. C19-RS had prognostic value for in-hospital mortality in COVID-19, with hazard ratios of 3.31 ([95%CI: 1.49–7.33], p=0.003) and 2.58 ([95%CI: 1.10–6.05], p=0.028) in two external testing cohorts respectively, after correction for clinical factors and biochemical biomarkers of inflammation (WBC, CRP) and myocardial injury (troponin). Importantly, the corrected HR for in-hospital mortality was 8.24[95%CI: 2.16–31.36], P=0.002 for those who received no treatment with dexamethasone, but only 2.27[95%CI: 0.69–7.55], p=0.18 in those who received dexamethasone after the test, suggesting that anti-inflammatory treatment may be modifying the natural history of COVID-19 infection by improving outcomes specifically in those patients with high vascular inflammation. Conclusions Our study introduces a new radiotranscriptomic signature, C19-RS, extracted from routine CTPAs, trained to detect cytokine-driven arterial inflammation, and demonstrates that vascular inflammation determined in this way has prognostic value in patients with COVID-19. The “UK variant” leads to higher vascular inflammation measured in this way, and the risk associated with COVID-19 arteritis is modifiable by dexamethasone.

This analysis evaluated the effect of semaglutide 2.4 mg vs. placebo (PBO) or semaglutide 1.0 mg on cardiometabolic risk in STEP 2, a double-blind, placebo-controlled trial in which 1210 adults with overweight/obesity and type 2 diabetes (T2D) were randomized 1:1:1 to 68 weeks’ once-weekly semaglutide 2.4 mg, 1.0 mg, or PBO, plus lifestyle intervention. Primary endpoints included percent change in body weight (BW). Secondary endpoints included change in cardiometabolic risk factors (including post-hoc analyses of non-high density lipoprotein cholesterol). Mean BW change from baseline to week 68 was −9.6% with semaglutide 2.4 mg vs. −3.4% with PBO (estimated treatment difference [ETD]: −6.2%; 95% CI: −7.3, −5.2; p Disclosure R. F. Kushner: Advisory Panel; Self; Novo Nordisk A/S. S. Verma: Advisory Panel; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Sanofi, Research Support; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Speaker’s Bureau; Self; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Eli Lilly and Company, EOCI Pharmacomm Ltd., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk, Sanofi, Sun Pharmaceutical Industries Ltd., Toronto Knowledge Translation Working Group. M. J. Davies: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Boehringer Ingelheim Limited (UK), Eli Lilly and Company, Lexicon Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi, Other Relationship; Self; AstraZeneca, NIHR Leicester Biomedical Research Centre, Novo Nordisk, Speaker’s Bureau; Self; Astra Zeneca Pharma India Ltd, Boehringer Ingelheim (China), Boehringer Ingelheim (Philippines), Inc., Boehringer Ingelheim International GmbH, Boehringer Ingelheim Limited (UK), Boehringer Ingelheim Saudi Arabia Trading, Boehringer Ingelheim Singapore Pte. Ltd, Boehringer Ingelheim Sp. Z o. o., Eli Lilly and Company, Napp Pharmaceuticals, Novo Nordisk, Novo Nordisk A/S, S. C. Sanofi Romania SRL, Sanofi K. K. J. Deanfield: None. W. Garvey: None. O. Jeppesen: Employee; Self; Novo Nordisk A/S, Employee; Spouse/Partner; Novo Nordisk A/S, Stock/Shareholder; Self; Novo Nordisk A/S, Stock/Shareholder; Spouse/Partner; Novo Nordisk A/S. U. Khalid: None. M. N. Kosiborod: Consultant; Self; Amgen Inc., Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novo Nordisk, Sanofi, Vifor Pharma Management Ltd., Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH. P. N. Laursen: Employee; Self; Novo Nordisk A/S. D. Rubino: Advisory Panel; Self; Novo Nordisk, Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk, Speaker’s Bureau; Self; Novo Nordisk, Stock/Shareholder; Self; Novo Nordisk. Funding Novo Nordisk A/S

Diabetes vascular complications, including cardiovascular disease, diabetic nephropathy and retinopathy, have a negative effect on the long-term prognosis of young people with type 1 diabetes mellitus (T1DM). Poor glycaemic control and consequent increased HbA1c levels are major risk factors for the development of vascular complications. HbA1c levels are the main focus of current management strategies; however, the recommended target is rarely achieved in adolescents. Thus, a clear need exists for improved biomarkers to identify high-risk young people early and to develop new intervention strategies. Evidence is accumulating that early increases in urinary albumin excretion could be predictive of adolescents with T1DM who are at an increased risk of developing vascular complications, independent of HbA1c levels. These findings present an opportunity to move towards the personalized care of adolescents with T1DM, which takes into consideration changes in albumin excretion and other risk factors in addition to HbA1c levels.

Endothelial dysfunction is involved in the development of atherosclerosis, which precedes asymptomatic structural vascular alterations as well as clinical manifestations of cardiovascular disease (CVD). Endothelial function can be assessed non-invasively using the flow-mediated dilation (FMD) technique. Flow-mediated dilation represents an endothelium-dependent, largely nitric oxide (NO)-mediated dilatation of conduit arteries in response to an imposed increase in blood flow and shear stress. Flow-mediated dilation is affected by cardiovascular (CV) risk factors, relates to coronary artery endothelial function, and independently predicts CVD outcome. Accordingly, FMD is a tool for examining the pathophysiology of CVD and possibly identifying subjects at increased risk for future CV events. Moreover, it has merit in examining the acute and long-term impact of physiological and pharmacological interventions in humans. Despite concerns about its reproducibility, the available evidence shows that highly reliable FMD measurements can be achieved when specialized laboratories follow standardized protocols. For this purpose, updated expert consensus guidelines for the performance of FMD are presented, which are based on critical appraisal of novel technical approaches, development of analysis software, and studies exploring the physiological principles underlying the technique. Uniformity in FMD performance will (i) improve comparability between studies, (ii) contribute to construction of reference values, and (iii) offer an easy accessible and early marker of atherosclerosis that could complement clinical symptoms of structural arterial disease and facilitate early diagnosis and prediction of CVD outcomes.

Aims We hypothesized that a decline in admissions with heart failure during COVID-19 pandemic would lead to a reciprocal rise in mortality for patients with heart failure in the community. Methods and results We used National Heart Failure Audit data to identify 36 974 adults who had a hospital admission with a primary diagnosis of heart failure between February and May in either 2018, 2019, or 2020. Hospital admissions for heart failure in 2018/19 averaged 160/day but were much lower in 2020, reaching a nadir of 64/day on 27 March 2020 [incidence rate ratio (IRR): 0.40, 95% confidence interval (CI): 0.38–0.42]. The proportion discharged on guideline-recommended pharmacotherapies was similar in 2018/19 compared to the same period in 2020. Between 1 February–2020 and 31 May 2020, there was a 29% decrease in hospital deaths related to heart failure (IRR: 0.71, 95% CI: 0.67–0.75; estimated decline of 448 deaths), a 31% increase in heart failure deaths at home (IRR: 1.31, 95% CI: 1.24–1.39; estimated excess 539), and a 28% increase in heart failure deaths in care homes and hospices (IRR: 1.28, 95% CI: 1.18–1.40; estimated excess 189). All-cause, inpatient death was similar in the COVID-19 and pre-COVID-19 periods [odds ratio (OR): 1.02, 95% CI: 0.94–1.10]. After hospital discharge, 30-day mortality was higher in 2020 compared to 2018/19 (OR: 1.57, 95% CI: 1.38–1.78). Conclusion Compared with the rolling daily average in 2018/19, there was a substantial decline in admissions for heart failure but an increase in deaths from heart failure in the community. Despite similar rates of prescription of guideline-recommended therapy, mortality 30 days from discharge was higher during the COVID-19 pandemic period.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): British Heart Foundation OnBehalf the CRISP-CT study investigators Introduction Non-invasive detection of coronary inflammation has the potential to improve targeting of cardiovascular prevention strategies. Coronary computed tomography angiography (CCTA)-based fat attenuation indexing (FAI) is a novel, validated measure of coronary inflammation that captures spatial changes in perivascular fat composition induced by coronary inflammation. However, to ensure accuracy, FAI values must be carefully standardized for technical, anatomical and biological factors before they are introduced for risk stratification in clinical practice. Purpose To validate the prognostic value of FAI-Score, the output of a new, artificial intelligence (AI)-powered algorithm, that harmonizes the FAI values of each coronary artery to generate a standardized metric of coronary inflammation for clinical use. Methods The study included 3912 individuals from the CRISP-CT study (2040 from the United States and 1872 from Europe) with a mean age of 55.7 (± standard deviation 13.7 years), 1608 (41.1%) of whom were women; all underwent clinically indicated CCTA. FAI-Score was measured at baseline in the proximal right coronary (RCA), left anterior descending (LAD) and left circumflex arteries (LCX) using the CaRi-Heart V1.1 platform (panel A). Percentile curves were created for the FAI-score of the RCA, LAD and LCX across different age and sex strata. Their prognostic value was further assessed in Cox models adjusted for hypertension, hyperlipidemia, diabetes mellitus, smoking, high-risk plaque features and the modified Duke prognostic coronary artery disease index. Results Over a median follow-up period of 5.6 years there were a total of 74 cardiac deaths. FAI-Score percentile curves were created to provide a population reference map for FAI-Score phenotyping of the three main coronary territories; LAD (panels B, C), RCA and LCX. There was a stepwise association between higher FAI-Score percentiles and the prospective risk of cardiac mortality across all three vessels analysed. When compared to individuals below the 50th percentile, those in the 90th percentile or higher had a 3.5-fold (LAD, panel D), 5.5-fold (RCA, panel E) and 2-fold (LCX, panel F) higher adjusted risk of cardiac mortality. Conclusion Coronary FAI-Score percentile curves provide a reference map for coronary inflammatory burden and enable standardized interpretation of perivascular FAI mapping on CCTA. Individuals in the top percentile curves have an increased cardiovascular risk independent of traditional risk factors and existing atherosclerotic changes. Abstract Figure.

Supplemental Digital Content is available in the text., Background: There is considerable interest in whether genetic data can be used to improve standard cardiovascular disease risk calculators, as the latter are routinely used in clinical practice to manage preventative treatment. Methods: Using the UK Biobank resource, we developed our own polygenic risk score for coronary artery disease (CAD). We used an additional 60 000 UK Biobank individuals to develop an integrated risk tool (IRT) that combined our polygenic risk score with established risk tools (either the American Heart Association/American College of Cardiology pooled cohort equations [PCE] or UK QRISK3), and we tested our IRT in an additional, independent set of 186 451 UK Biobank individuals. Results: The novel CAD polygenic risk score shows superior predictive power for CAD events, compared with other published polygenic risk scores, and is largely uncorrelated with PCE and QRISK3. When combined with PCE into an IRT, it has superior predictive accuracy. Overall, 10.4% of incident CAD cases were misclassified as low risk by PCE and correctly classified as high risk by the IRT, compared with 4.4% misclassified by the IRT and correctly classified by PCE. The overall net reclassification improvement for the IRT was 5.9% (95% CI, 4.7–7.0). When individuals were stratified into age-by-sex subgroups, the improvement was larger for all subgroups (range, 8.3%–15.4%), with the best performance in 40- to 54-year-old men (15.4% [95% CI, 11.6–19.3]). Comparable results were found using a different risk tool (QRISK3) and also a broader definition of cardiovascular disease. Use of the IRT is estimated to avoid up to 12 000 deaths in the United States over a 5-year period. Conclusions: An IRT that includes polygenic risk outperforms current risk stratification tools and offers greater opportunity for early interventions. Given the plummeting costs of genetic tests, future iterations of CAD risk tools would be enhanced with the addition of a person’s polygenic risk.

Background and objectiveThe impact of the COVID-19 pandemic on the quality of care for patients with acute myocardial infarction (AMI) is uncertain. We aimed to compare quality of AMI care in England and Wales during and before the COVID-19 pandemic using the 2020 European Society of Cardiology Association for Acute Cardiovascular Care quality indicators (QIs) for AMI.MethodsCohort study of linked data from the AMI and the percutaneous coronary intervention registries in England and Wales between 1 January 2017 and 27 May 2020 (representing 236 743 patients from 186 hospitals). At the patient level, the likelihood of attainment for each QI compared with pre COVID-19 was calculated using logistic regression. The date of the first national lockdown in England and Wales (23 March 2020) was chosen for time series comparisons.ResultsThere were 10 749 admissions with AMI after 23 March 2020. Compared with before the lockdown, patients admitted with AMI during the first wave had similar age (mean 68.0 vs 69.0 years), with no major differences in baseline characteristics (history of diabetes (25% vs 26%), renal failure (6.4% vs 6.9%), heart failure (5.8% vs 6.4%) and previous myocardial infarction (22.9% vs 23.7%)), and less frequently had high Global Registry of Acute Coronary Events risk scores (43.6% vs 48.6%). There was an improvement in attainment for 10 (62.5%) of the 16 measured QIs including a composite QI (43.8% to 45.2%, OR 1.06, 95% CI 1.02 to 1.10) during, compared with before, the lockdown.ConclusionDuring the first wave of the COVID-19 pandemic in England and Wales, quality of care for AMI as measured against international standards did not worsen, but improved modestly.

ObjectiveThere are concerns that healthcare and outcomes of black, Asian and minority ethnic (BAME) communities are disproportionately impacted by the COVID-19 pandemic. We investigated admission rates, treatment and mortality of BAME with acute myocardial infarction (AMI) during COVID-19.MethodsUsing multisource national healthcare records, patients hospitalised with AMI in England during 1 February–27 May 2020 were included in the COVID-19 group, whereas patients admitted during the same period in the previous three consecutive years were included in a pre-COVID-19 group. Multilevel hierarchical regression analyses were used to quantify the changes in-hospital and 7-day mortality in BAME compared with whites.ResultsOf 73 746 patients, higher proportions of BAME patients (16.7% vs 10.1%) were hospitalised with AMI during the COVID-19 period compared with pre-COVID-19. BAME patients admitted during the COVID-19 period were younger, male and likely to present with ST-elevation acute myocardial infarction. COVID-19 BAME group admitted with non-ST-elevation acute myocardial infarction less frequently received coronary angiography (86.1% vs 90.0%, pConclusionIn this multisource linked cohort study, compared with whites, BAME patients had proportionally higher hospitalisation rates with AMI, less frequently received guidelines indicated care and had higher early mortality during COVID-19 period compared with pre-COVID-19 period. There is a need to develop clinical pathways to achieve equity in the management of these vulnerable populations.

Background Aortic stiffness is closely linked with cardiovascular diseases (CVDs), but recent studies suggest that it is also a risk factor for cognitive decline and dementia. However, the brain changes underlying this risk are unclear. We examined whether aortic stiffening during a 4-year follow-up in mid-to-late life was associated with brain structure and cognition in the Whitehall II Imaging Sub-study. Methods and findings The Whitehall II Imaging cohort is a randomly selected subset of the ongoing Whitehall II Study, for which participants have received clinical follow-ups for 30 years, across 12 phases. Aortic pulse wave velocity (PWV) was measured in 2007–2009 (Phase 9) and at a 4-year follow-up in 2012–2013 (Phase 11). Between 2012 and 2016 (Imaging Phase), participants received a multimodal 3T brain magnetic resonance imaging (MRI) scan and cognitive tests. Participants were selected if they had no clinical diagnosis of dementia and no gross brain structural abnormalities. Voxel-based analyses were used to assess grey matter (GM) volume, white matter (WM) microstructure (fractional anisotropy (FA) and diffusivity), white matter lesions (WMLs), and cerebral blood flow (CBF). Cognitive outcomes were performance on verbal memory, semantic fluency, working memory, and executive function tests. Of 542 participants, 444 (81.9%) were men. The mean (SD) age was 63.9 (5.2) years at the baseline Phase 9 examination, 68.0 (5.2) at Phase 11, and 69.8 (5.2) at the Imaging Phase. Voxel-based analysis revealed that faster rates of aortic stiffening in mid-to-late life were associated with poor WM microstructure, viz. lower FA, higher mean, and radial diffusivity (RD) in 23.9%, 11.8%, and 22.2% of WM tracts, respectively, including the corpus callosum, corona radiata, superior longitudinal fasciculus, and corticospinal tracts. Similar voxel-wise associations were also observed with follow-up aortic stiffness. Moreover, lower mean global FA was associated with faster rates of aortic stiffening (B = −5.65, 95% CI −9.75, −1.54, Bonferroni-corrected p < 0.0125) and higher follow-up aortic stiffness (B = −1.12, 95% CI −1.95, −0.29, Bonferroni-corrected p < 0.0125). In a subset of 112 participants who received arterial spin labelling scans, faster aortic stiffening was also related to lower cerebral perfusion in 18.4% of GM, with associations surviving Bonferroni corrections in the frontal (B = −10.85, 95% CI −17.91, −3.79, p < 0.0125) and parietal lobes (B = −12.75, 95% CI −21.58, −3.91, p < 0.0125). No associations with GM volume or WMLs were observed. Further, higher baseline aortic stiffness was associated with poor semantic fluency (B = −0.47, 95% CI −0.76 to −0.18, Bonferroni-corrected p < 0.007) and verbal learning outcomes (B = −0.36, 95% CI −0.60 to −0.12, Bonferroni-corrected p < 0.007). As with all observational studies, it was not possible to infer causal associations. The generalisability of the findings may be limited by the gender imbalance, high educational attainment, survival bias, and lack of ethnic and socioeconomic diversity in this cohort. Conclusions Our findings indicate that faster rates of aortic stiffening in mid-to-late life were associated with poor brain WM microstructural integrity and reduced cerebral perfusion, likely due to increased transmission of pulsatile energy to the delicate cerebral microvasculature. Strategies to prevent arterial stiffening prior to this point may be required to offer cognitive benefit in older age. Trial registration ClinicalTrials.gov NCT03335696, Sana Suri and colleagues investigate differences in brain structure and connectivity associated with aortic stiffening in older adults., Author summary Why was this study done? Stiffening of large arteries such as the aorta has been closely linked to the onset of heart diseases, but recent studies show that this may also increase risk for dementia. Understanding the brain changes which underlie this risk could help identify strategies to prevent or delay dementia in old age. What did the researchers do and find? We investigated 542 community-dwelling older adults who received 2 measurements of aortic stiffness, first at approximately 64 years old and again at approximately 68 years old. Shortly after that, at mean age 69 years, they underwent cognitive tests and brain magnetic resonance imaging (MRI) scans to assess the size, connections, and blood supply of different brain regions. We observed that a faster rate of aortic stiffening during the 4 years in mid-to-late life was linked to lower blood flow and poorer markers of brain connectivity across several brain regions. We also found that lower memory performance in older age was most closely linked to the first measures of aortic stiffness, taken at baseline, rather than the later measures of stiffness. What do these findings mean? Faster stiffening of the aorta in mid-to-older ages may influence brain health, specifically, the brain’s delicate blood vessels and the connectivity between different brain regions. However, in order to benefit memory in older age, strategies to prevent or slow down arterial stiffening may be required even earlier in the life span. Although this was a large study, it was conducted in a relatively well-educated and largely male sample, so future research on more representative samples are needed to allow us to generalise the findings to the wider population.