Major Adverse Cardiovascular Events Following Coronary Artery Stenting by History of Hypertensive Disorder of Pregnancy.

BACKGROUND: A history of hypertensive disorders of pregnancy is associated with at least twice the risk of incident ischemic heart disease. Whether the long-term outcome following treatment with coronary artery stenting is associated to the history of hypertensive disorders of pregnancy is unknown. METHODS AND RESULTS: We included 8364 women (age ≤65 years) undergoing first coronary artery stenting 2006 to 2022 following their first delivery in 1973 or later, linking nationwide data on percutaneous coronary intervention and delivery history. In total, 1122 women (13.4%) had a history of hypertensive disorders of pregnancy. The main outcome, a major adverse cardiovascular event, was defined as any incident myocardial infarction, ischemic heart disease, cardiac arrest, arrhythmias, angina pectoris, heart failure, cerebral infarction, or sudden death. During a median follow-up time of 5 years, 258 women with a history of hypertensive disorders of pregnancy had a major adverse cardiovascular event, compared with 1465 women without a history of hypertensive disorders of pregnancy (23% versus 20.2%, P=0.028 for log-rank test). Estimates adjusted for patient- and procedural characteristics in proportional hazards regression models suggested that the hazard rate increased only after 4-8 years of follow-up (hazard ratio [HR], 1.36 [95% CI, 1.05-1.78]) and was primarily driven by women with history of gestational hypertension (HR, 2.15 [95% CI, 1.49-3.11]). CONCLUSIONS: Women with a history of hypertensive disorders of pregnancy have an increased risk of a major adverse cardiovascular event following coronary artery stenting compared with other parous women. A history of hypertensive disorders of pregnancy warrants further attention in the secondary prevention setting of coronary artery disease.

Elevated carbohydrate antigen 125 (CA125) is associated with incident heart failure and mortality in acute coronary syndrome.

AIMS: Carbohydrate antigen 125 (CA125), a mucin produced by serosal cells in response to mechanical and inflammatory stimuli, has emerged as an important biomarker to guide risk stratification in heart failure (HF). The prognostic value of CA125 in acute coronary syndrome (ACS) patients is less explored. METHODS: In a cohort of 524 ACS patients (73% males, mean age 67 ± 12 years), we assessed the associations between CA125 and the risk for HF and death during a median follow-up period of 27.3 months for incident HF and 39.5 months for mortality. Plasma CA125 was measured within 24 h after admission in the entire cohort and after 6 weeks in a subgroup of 115 elderly patients (>75 years of age). We also assessed the relationships between baseline CA125 and echocardiographic parameters of cardiac structure and function at 1 year post-ACS in this subgroup. RESULTS: Baseline CA125 was associated with incident HF in the entire cohort in a Cox proportional hazards model adjusted for age, sex, cardiovascular (CV) risk factors (diabetes, smoking, hypertension, previous HF, previous ACS and previous stroke), renal function and revascularization {hazard ratio [HR] 1.46 [95% confidence interval (CI) 1.10-1.93] per 1-standard deviation [SD] CA125 increase; P = 0.009}. In the detailed follow-up subgroup, elevated baseline CA125 predicted subsequent deterioration of left ventricular (LV) ejection fraction (LVEF), defined as a >5% absolute LVEF decrease in patients with LVEF ≥ 50% at discharge [odds ratio (OR) 3.31 (95% CI 1.15-9.54) per 1-SD baseline CA125 increase; P = 0.027]. We also found significant correlations between high baseline CA125 and larger LV volumes (LV end-diastolic volume index, Spearman's r = 0.329, P < 0.001; LV end-systolic volume index, r = 0.391, P < 0.001) and left atrial volume index (r = 0.320, P < 0.001) at 1 year post-ACS, indicative of adverse cardiac remodelling. Elevated baseline and follow-up CA125 were associated with increased mortality, independently of age and sex [HR 1.37 (95% CI 1.09-1.71), P = 0.006, per 1-SD baseline CA125; HR 1.98 (95% CI 1.06-3.67), P = 0.031, per increasing 6 week CA125 tertile]. The relationship between 6 week CA125 and incident mortality remained significant in the fully adjusted model [HR 2.23 (95% CI 1.15-4.35) per increasing CA125 tertile; P = 0.018]. CONCLUSIONS: We report independent associations between elevated CA125, LV dysfunction, cardiac remodelling, incident HF and mortality post-ACS. Our results warrant further evaluation of CA125 as a potential biomarker for risk stratification and management of ACS patients, both at the time of the acute coronary event and during follow-up.

An organic-organometallic CO-releasing material comprising 4,4'-bipyridine and molybdenum subcarbonyl building blocks.

Over the past two decades, following the discovery of the important biological roles of carbon monoxide (CO), metal carbonyl complexes have been intensively studied as CO-releasing molecules (CORMs) for therapeutic applications. To improve the properties of "bare" low molecular weight CORMs, attention has been drawn to conjugating CORMs with macromolecular and inorganic scaffolds to produce CO-releasing materials (CORMAs) capable of storing and delivering large payloads of the gasotransmitter. A significant obstacle is to obtain CORMAs that retain the beneficial features of the parent CORMs. In the present work, a crystalline metal-organic framework (MOF) formulated as Mo(CO)3(4,4'-bipyridine)3/2 (Mobpy), with a structure based on Mo(CO)3 metallic nodes and bipyridine linkers, has been prepared in near quantitative yield by a straightforward reflux method, and found to exhibit CO-release properties that mimic those typically observed for molybdenum carbonyl CORMs. Mobpy was characterized by powder X-ray diffraction (PXRD), thermogravimetric analysis (TGA), FT-IR, FT-Raman and diffuse reflectance (DR) UV-vis spectroscopies, and 13C{1H} cross-polarization (CP) magic-angle spinning (MAS) NMR. The release of CO from Mobpy was studied by the deoxy-myoglobin (deoxy-Mb)/carbonmonoxy-myoglobin (MbCO) UV-vis assay. Mobpy liberates CO upon contact with a physiological buffer in the dark, leading to a maximum released amount of 1.3-1.5 mmol g-1, after 1.5 h at 37 °C, with half-lives of 0.5-1.0 h (time to transfer 0.5 equiv. of CO to Mb). In the solid-state and under open air, Mobpy undergoes complete decarbonylation over a period of 42 days, corresponding to a theoretical CO-release of 7.25 mmol g-1.

Self-Report Tool for Identification of Individuals With Coronary Atherosclerosis: The Swedish CardioPulmonary BioImage Study.

BACKGROUND: Coronary atherosclerosis detected by imaging is a marker of elevated cardiovascular risk. However, imaging involves large resources and exposure to radiation. The aim was, therefore, to test whether nonimaging data, specifically data that can be self-reported, could be used to identify individuals with moderate to severe coronary atherosclerosis. METHODS AND RESULTS: We used data from the population-based SCAPIS (Swedish CardioPulmonary BioImage Study) in individuals with coronary computed tomography angiography (n=25 182) and coronary artery calcification score (n=28 701), aged 50 to 64 years without previous ischemic heart disease. We developed a risk prediction tool using variables that could be assessed from home (self-report tool). For comparison, we also developed a tool using variables from laboratory tests, physical examinations, and self-report (clinical tool) and evaluated both models using receiver operating characteristic curve analysis, external validation, and benchmarked against factors in the pooled cohort equation. The self-report tool (n=14 variables) and the clinical tool (n=23 variables) showed high-to-excellent discriminative ability to identify a segment involvement score ≥4 (area under the curve 0.79 and 0.80, respectively) and significantly better than the pooled cohort equation (area under the curve 0.76, P<0.001). The tools showed a larger net benefit in clinical decision-making at relevant threshold probabilities. The self-report tool identified 65% of all individuals with a segment involvement score ≥4 in the top 30% of the highest-risk individuals. Tools developed for coronary artery calcification score ≥100 performed similarly. CONCLUSIONS: We have developed a self-report tool that effectively identifies individuals with moderate to severe coronary atherosclerosis. The self-report tool may serve as prescreening tool toward a cost-effective computed tomography-based screening program for high-risk individuals.

Reservoir-excess pressure parameters are independently associated with NT-proBNP in older adults.

AIMS: Parameters derived from reservoir-excess pressure analysis have been demonstrated to predict cardiovascular events. Thus, altered reservoir-excess pressure parameters could have a detrimental effect on highly-perfused organs like the heart. We aimed to cross-sectionally determine whether reservoir-excess pressure parameters were associated with N-terminal pro-brain-type natriuretic peptide (NT-proBNP) in older adults. METHODS: We studied 868 older adults with diverse cardiovascular risk. Reservoir-excess pressure parameters were obtained through radial artery tonometry including reservoir pressure integral, peak reservoir pressure, excess pressure integral (INTXSP), systolic rate constant (SRC) and diastolic rate constant (DRC). Plasma levels of NT-proBNP, as a biomarker of cardiac overload, were analysed by the Proximity Extension Assay technology. RESULTS: Multivariable linear regression analyses revealed that all reservoir-excess pressure parameters studied were associated with NT-proBNP after adjusting for age and sex. After further adjustments for conventional cardiovascular risk factors, INTXSP [ß = 0.191 (95% confidence interval, CI: 0.099, 0.283), P < 0.001], SRC [ß = -0.080 (95% CI: -0.141, -0.019), P = 0.010] and DRC [ß = 0.138 (95% CI: 0.073, 0.202), P < 0.001] remained associated with NT-proBNP. Sensitivity analysis found that there were occasions where the association between SRC and NT-proBNP was attenuated, but both INTXSP and DRC remained consistently associated with NT-proBNP. CONCLUSIONS: The observed associations between reservoir-excess pressure parameters and NT-proBNP suggest that altered reservoir-excess pressure parameters may reflect an increased load inflicted on the left ventricular cardiomyocytes and could have a potential to be utilized in the clinical setting for cardiovascular risk stratification.

ADAM-17 Activity and Its Relation to ACE2: Implications for Severe COVID-19.

There is a lack of studies aiming to assess cellular a disintegrin and metalloproteinase-17 (ADAM-17) activity in COVID-19 patients and the eventual associations with the shedding of membrane-bound angiotensin-converting enzyme 2 (mACE2). In addition, studies that investigate the relationship between ACE2 and ADAM-17 gene expressions in organs infected by SARS-CoV-2 are lacking. We used data from the Massachusetts general hospital COVID-19 study (306 COVID-19 patients and 78 symptomatic controls) to investigate the association between plasma levels of 33 different ADAM-17 substrates and COVID-19 severity and mortality. As a surrogate of cellular ADAM-17 activity, an ADAM-17 substrate score was calculated. The associations between soluble ACE2 (sACE2) and the ADAM-17 substrate score, renin, key inflammatory markers, and lung injury markers were investigated. Furthermore, we used data from the Genotype-Tissue Expression (GTEx) database to evaluate ADAM-17 and ACE2 gene expressions by age and sex in ages between 20-80 years. We found that increased ADAM-17 activity, as estimated by the ADAM-17 substrates score, was associated with COVID-19 severity (p = 0.001). ADAM-17 activity was also associated with increased mortality but did not reach statistical significance (p = 0.06). Soluble ACE2 showed the strongest positive correlation with the ADAM-17 substrate score, follow by renin, interleukin-6, and lung injury biomarkers. The ratio of ADAM-17 to ACE2 gene expression was highest in the lung. This study indicates that increased ADAM-17 activity is associated with severe COVID-19. Our findings also indicate that there may a bidirectional relationship between membrane-bound ACE2 shedding via increased ADAM-17 activity, dysregulated renin-angiotensin system (RAS) and immune signaling. Additionally, differences in ACE2 and ADAM-17 gene expressions between different tissues may be of importance in explaining why the lung is the organ most severely affected by COVID-19, but this requires further evaluation in prospective studies.

Circadian ABCG2 Expression Influences the Brain Uptake of Donepezil across the Blood-Cerebrospinal Fluid Barrier.

Donepezil (DNPZ) is a cholinesterase inhibitor used for the management of Alzheimer's disease (AD) and is dependent on membrane transporters such as ABCG2 to actively cross brain barriers and reach its target site of action in the brain. Located in the brain ventricles, the choroid plexus (CP) forms an interface between the cerebrospinal fluid (CSF) and the bloodstream, known as the blood-CSF barrier (BCSFB). Historically, the BCSFB has received little attention as a potential pathway for drug delivery to the central nervous system (CNS). Nonetheless, this barrier is presently viewed as a dynamic transport interface that limits the traffic of molecules into and out of the CNS through the presence of membrane transporters, with parallel activity with the BBB. The localization and expression of drug transporters in brain barriers represent a huge obstacle for drug delivery to the brain and a major challenge for the development of therapeutic approaches to CNS disorders. The widespread interest in understanding how circadian clocks modulate many processes that define drug delivery in order to predict the variability in drug safety and efficacy is the next bridge to improve effective treatment. In this context, this study aims at characterizing the circadian expression of ABCG2 and DNPZ circadian transport profile using an in vitro model of the BCSFB. We found that ABCG2 displays a circadian pattern and DNPZ is transported in a circadian way across this barrier. This study will strongly impact on the capacity to modulate the BCSFB in order to control the penetration of DNPZ into the brain and improve therapeutic strategies for the treatment of AD according to the time of the day.

The Gly82Ser polymorphism in the receptor for advanced glycation endproducts increases the risk for coronary events in the general population.

The receptor for advanced glycation endproducts (RAGE) has pro-inflammatory and pro-atherogenic effects. Low plasma levels of soluble RAGE (sRAGE), a decoy receptor for RAGE ligands, have been associated with increased risk for major adverse coronary events (MACE) in the general population. We performed a genome-wide association study to identify genetic determinants of plasma sRAGE in 4338 individuals from the cardiovascular arm of the Malmö Diet and Cancer study (MDC-CV). Further, we explored the associations between these genetic variants, incident first-time MACE and mortality in 24,640 unrelated individuals of European ancestry from the MDC cohort. The minor alleles of four single nucleotide polymorphisms (SNPs): rs2070600, rs204993, rs116653040, and rs7306778 were independently associated with lower plasma sRAGE. The minor T (vs. C) allele of rs2070600 was associated with increased risk for MACE [HR 1.13 95% CI (1.02-1.25), P = 0.016]. Neither SNP was associated with mortality. This is the largest study to demonstrate a link between a genetic sRAGE determinant and CV risk. Only rs2070600, which enhances RAGE function by inducing a Gly82Ser polymorphism in the ligand-binding domain, was associated with MACE. The lack of associations with incident MACE for the other sRAGE-lowering SNPs suggests that this functional RAGE modification is central for the observed relationship.

Prognostic Markers in Pediatric Acute Liver Failure.

Introduction: Acute liver failure (ALF), although rare in children, is a complex progressive pathology, with multisystem involvement and high mortality. Isolated variables or those included in prognostic scores have been studied, to optimize organ allocation. However, its validation is challenging. This study aimed to assess the accuracy of several biomarkers and scores as predictors of prognosis in pediatric ALF (PALF). Methods: An observational study with retrospective data collection, including all cases of ALF, was defined according to the criteria of the Pediatric Acute Liver Failure Study Group, admitted to a pediatric intensive care unit (PICU) for 28 years. Two groups were defined: spontaneous recovery (SR) and non-SR (NSR) - submitted to liver transplantation (LT) or death at PICU discharge. Results: Fifty-nine patients were included, with a median age of 24 months, and 54% were female. The most frequent etiologies were metabolic (25.4%) and infectious (18.6%); 32.2% were undetermined. SR occurred in 21 patients (35.6%). In NSR group (N = 38, 64.4%), 25 required LT (42.4%) and 19 died (32.2%), 6 (15.7%) of whom after LT. The accuracy to predict NSR was acceptable for lactate at admission (AUC 0.72; 95% CI: 0.57-0.86; p = 0.006), ammonia peak (AUC 0.72; 95% CI: 0.58-0.86; p = 0.006), and INR peak (AUC 0.70; 95% CI: 0.56-0.85; p = 0.01). The cut-off value for lactate at admission was 1.95 mmol/L (sensitivity 78.4% and specificity 61.9%), ammonia peak was 64 µmol/L (sensitivity 100% and specificity 38.1%), and INR peak was 4.8 (sensitivity 61.1% and specificity 76.2%). Lactate on admission was shown to be an independent predictor of NSR on logistic regression model. Two prognostic scores had acceptable discrimination for NSR, LIU (AUC 0.73; 95% CI: 0.59-0.87; p = 0.004) and PRISM (AUC 0.71; 95% CI: 0.56-0.86; p = 0.03). In our study, the PALF delta score (PALF-ds) had lower discrimination capacity (AUC 0.63; 95% CI: 0.47-0.78; p = 0.11). Conclusions: The lactate at admission, an easily obtained parameter, had a similar capacity than the more complex scores, LIU and PRISM, to predict NSR. The prognostic value in our population of the promising dynamic score, PALF-ds, was lower than expected.

Introdução: A falência hepática aguda (FHA), apesar de rara em pediatria, é uma patologia complexa, com envolvimento multissistémico e elevada mortalidade. Têm sido estudadas variáveis isoladas ou incluídas em scores de prognóstico, com o objetivo de otimizar a alocação de órgãos. No entanto, a sua validação apresenta alguns desafios. O presente estudo tem como objetivo avaliar a precisão de vários biomarcadores e scores, como preditores de prognóstico na FHA. Métodos: Estudo observacional com método de colheita de dados retrospetivo, tendo como critérios de inclusão os casos de FHA, definida de acordo com os critérios da Pediatric Acute Liver Failure Study Group, admitidos numa Unidade de Cuidados Intensivos Pediátricos (UCIP) num período de 28 anos. Definiram-se 2 grupos: recuperação espontânea (RE) e sem recuperação espontânea (SRE) ­ doentes submetidos a transplante hepático (TRH) ou morte na alta da UCIP. Resultados: Incluíram-se 59 doentes, com mediana de idade de 24 meses, 54% do sexo feminino. As etiologias mais frequentes foram a metabólica (25.4%) e a infeciosa (18.6%); em 32.2% foi indeterminada. Apresentaram RE 21 doentes (35.6%). No grupo SRE (N = 38, 64.4%), 25 necessitaram de TRH (42.4%) e 19 faleceram (32.2%), dos quais 6 (15.7%) tinham sido submetidos a TRH. A precisão prognóstica para a ausência de recuperação espontânea foi aceitável para o lactato na admissão (AUC 0.72; IC 95%: 0.57­0.86; p = 0.006), amónia máxima (AUC 0.72; IC 95%: 0.58­0.86; p = 0.006) e INR máximo (AUC 0.70; IC 95%: 0.56­0.85; p = 0.01). O valor de cut-off do lactato na admissão foi de 1.95 mmol/L (sensibilidade 78.4% e especificidade 61.9%) e da amónia máxima foi de 64 umol/L (sensibilidade 100% e especificidade 38.1%). O lactato à admissão mostrou ser um fator independente para NSR, no modelo de regressão logística. Os scores LIU e PRISM apresentaram curvas ROC com aceitável capacidade de discriminação para a ausência de recuperação espontânea, com AUC de 0.73 (IC 95%: 0.59­0.87; p = 0.004) e 0.71 (IC 95%: 0.56­0.86; p = 0.03), respetivamente. No nosso estudo, o score PALF-Delta (PALF-ds) teve uma menor capacidade de discriminação (AUC 0.63; IC 95%: 0.47­0.78; p = 0.11). Conclusões: O lactato na admissão, um parâmetro de fácil obtenção, teve uma capacidade semelhante aos scores mais complexos, LIU e PRISM, para predizer a ausência de recuperação espontânea. O valor prognóstico nesta série, do promissor score dinâmico PALF-ds, foi inferior ao esperado.

Atherosclerotic plaque features relevant to rupture-risk detected by clinical photon-counting CT ex vivo: a proof-of-concept study.

BACKGROUND: To identify subjects with rupture-prone atherosclerotic plaques before thrombotic events occur is an unmet clinical need. Thus, this proof-of-concept study aims to determine which rupture-prone plaque features can be detected using clinically available photon-counting computed tomography (PCCT). METHODS: In this retrospective study, advanced atherosclerotic plaques (ex vivo, paraffin-embedded) from the Carotid Plaque Imaging Project were scanned by PCCT with reconstructed energy levels (45, 70, 120, 190 keV). Density in HU was measured in 97 regions of interest (ROIs) representing rupture-prone plaque features as demonstrated by histopathology (thrombus, lipid core, necrosis, fibrosis, intraplaque haemorrhage, calcium). The relationship between HU and energy was then assessed using a mixed-effects model for each plaque feature. RESULTS: Plaques from five men (age 79 ± 8 [mean ± standard deviation]) were included in the study. Comparing differences in coefficients (b1diff) of matched ROIs on plaque images obtained by PCCT and histology confirmed that calcium was distinguishable from all other analysed features. Of greater novelty, additional rupture-prone plaque features proved discernible from each other, particularly when comparing haemorrhage with fibrous cap (p = 0.017), lipids (p = 0.003) and necrosis (p = 0.004) and thrombus compared to fibrosis (p = 0.048), fibrous cap (p = 0.028), lipids (p = 0.015) and necrosis (p = 0.017). CONCLUSIONS: Clinically available PCCT detects not only calcification, but also other rupture-prone features of human carotid plaques ex vivo. RELEVANCE STATEMENT: Improved atherosclerotic plaque characterisation by photon-counting CT provides the ability to distinguish not only calcium, but also rupture-prone plaque features such as haemorrhage and thrombus. This may potentially improve monitoring and risk stratification of atherosclerotic patients in order to prevent strokes. KEY POINTS: • CT of atherosclerotic plaques mainly detects calcium. • Many components, such as intra-plaque haemorrhage and lipids, determine increased plaque rupture risk. • Ex vivo carotid plaque photon-counting CT distinguishes haemorrhage and thrombus. • Improved plaque photon-counting CT evaluation may refine risk stratification accuracy to prevent strokes.

Type 2 diabetes exacerbates changes in blood pressure-independent arterial stiffness: cross-sectional and longitudinal evidence from the SUMMIT study.

Greater central artery stiffness is observed in people with type 2 diabetes (T2DM). Elevated blood pressure (BP) and altered arterial wall structure/composition in T2DM are generally considered as main drivers for this alteration. However, because conventional arterial stiffness measures are BP-dependent and as such an influence of BP remains in a measure, it is unclear if greater central artery stiffness is a function of greater BP, or due to changes in the structure and composition of the arterial wall. We aimed to measure BP-independent arterial stiffness (ß0) cross-sectionally and longitudinally in T2DM. We studied 753 adults with T2DM (DM+) and 436 adults without (DM-) at baseline (Phase 1), and 310 DM+ and 210 DM- adults at 3-yr follow-up (Phase 2). We measured carotid-femoral pulse wave velocity and used it to calculate ß0. In Phase 1, ß0 was significantly greater in DM+ than DM- after adjusting for age and sex [27.5 (26.6-28.3) vs. 23.6 (22.4-24.8) au, P < 0.001]. Partial correlation analyses after controlling for age and sex showed that ß0 was significantly associated with hemoglobin A1c (r = 0.15 P < 0.001) and heart rate [(HR): r = 0.23 P < 0.001)] in DM+. In Phase 2, percentage-change in ß0 was significantly greater in DM+ than DM- [19.5 (14.9-24.0) vs. 5.0 (-0.6 to 10.6) %, P < 0.001] after adjusting for age, sex, and baseline ß0. ß0 was greater in DM+ than DM- and increased much more in DM+ than in DM- over 3 yr. This suggests that T2DM exacerbates BP-independent arterial stiffness and may have a complemental utility to existing arterial stiffness indices.NEW & NOTEWORTHY We demonstrate in this study a greater BP-independent arterial stiffness ß0 in people with type 2 diabetes (T2DM) compared to those without, and also a greater change in ß0 over 3 yr in people with T2DM than those without. These findings suggest that the intrinsic properties of the arterial wall may change in a different and more detrimental way in people with T2DM and likely represents accumulation of cardiovascular risk.

Plasma levels of PRO-C3, a type III collagen synthesis marker, are associated with arterial stiffness and increased risk of cardiovascular death.

BACKGROUND AND AIMS: The N-terminal propeptide of type III collagen (PRO-C3) assay measures a pro-peptide released during type III collagen synthesis, an important feature of arterial stiffening and atherogenesis. There is a clinical need for improved non-invasive, cheap and easily accessible methods for evaluating individuals at risk of cardiovascular disease (CVD). In this study, we investigate the potential of using circulating levels of PRO-C3 to mark the degree of vascular stenosis and risk of cardiovascular events. METHODS: Baseline plasma levels of PRO-C3 were measured by ELISA in subjects belonging to the SUrrogate markers for Micro- and Macro-vascular hard endpoints for Innovative diabetes Tools (SUMMIT) cohort (N = 1354). Associations between PRO-C3 levels with vascular characteristics, namely stiffness and stenosis, and risk of future cardiovascular events were explored. Subjects were followed up after a median of 35 months (interquartile range 34-36 months), with recorded outcomes cardiovascular death and all-cause mortality. RESULTS: We found a correlation between PRO-C3 levels and pulse wave velocity (rho 0.13, p = 0.000009), a measurement of arterial stiffness. Higher PRO-C3 levels were also associated with elevated blood pressure (rho 0.07, p = 0.014), as well as risk of cardiovascular mortality over a three-year follow-up period (OR 1.56, confidence interval 1.008-2.43, p = 0.046). CONCLUSIONS: Elevated circulating PRO-C3 levels are associated with arterial stiffness and future cardiovascular death, in the SUMMIT cohort, suggesting a potential value of PRO-C3 as a novel marker for declining vascular health.

Red cell distribution width and its polygenic score in relation to mortality and cardiometabolic outcomes.

Introduction: Elevated red cell distribution width (RDW) has been associated with a range of health outcomes. This study aims to examine prognostic and etiological roles of RDW levels, both phenotypic and genetic predisposition, in predicting cardiovascular outcomes, diabetes, chronic kidney disease (CKD) and mortality. Methods: We studied 27,141 middle-aged adults from the Malmö Diet and Cancer study (MDCS) with a mean follow up of 21 years. RDW was measured with a hematology analyzer on whole blood samples. Polygenic scores for RDW (PGS-RDW) were constructed for each participant using genetic data in MDCS and published summary statistics from genome-wide association study of RDW (n = 408,112). Cox proportional hazards regression was used to assess associations between RDW, PGS-RDW and cardiovascular outcomes, diabetes, CKD and mortality, respectively. Results: PGS-RDW was significantly associated with RDW (Pearson's correlation coefficient = 0.133, p < 0.001). RDW was significantly associated with incidence of stroke (hazard ratio (HR) per 1 standard deviation = 1.06, 95% confidence interval (CI): 1.02-1.10, p = 0.003), atrial fibrillation (HR = 1.09, 95% CI: 1.06-1.12, p < 0.001), heart failure (HR = 1.13, 95% CI: 1.08-1.19, p < 0.001), venous thromboembolism (HR = 1.21, 95% CI: 1.15-1.28, p < 0.001), diabetes (HR = 0.87, 95% CI: 0.84-0.90, p < 0.001), CKD (HR = 1.08, 95% CI: 1.03-1.13, p = 0.004) and all-cause mortality (HR = 1.18, 95% CI: 1.16-1.20, p < 0.001). However, PGS-RDW was significantly associated with incidence of diabetes (HR = 0.96, 95% CI: 0.94-0.99, p = 0.01), but not with any other tested outcomes. Discussion: RDW is associated with mortality and incidence of cardiovascular diseases, but a significant association between genetically determined RDW and incident cardiovascular diseases were not observed. However, both RDW and PGS-RDW were inversely associated with incidence of diabetes, suggesting a putative causal relationship. The relationship with incidence of diabetes needs to be further studied.

Invariant natural killer T cells and incidence of first-time coronary events: a nested case-control study.

Aims: Invariant natural killer T (iNKT) cells, a T cell subset that is CD1d-restricted and expresses a semi-invariant T cell receptor, have been proposed to contribute to dyslipidaemia-driven cardiovascular disease due to their ability to specifically recognize lipid antigens. Studies in mice have attributed pro-atherogenic properties to iNKT cells, but studies in humans investigating associations of iNKT cells with incident coronary events (CE) are lacking. Methods and results: Here, we used flow cytometry to enumerate circulating iNKT cells (CD3+ CD1d-PBS57-Tetramer+) in a case-control cohort nested within the prospective population-based Malmö Diet and Cancer Study (n = 416) to explore associations with incident first-time CE during a median follow-up of 14 years. We found a significant inverse association between CD4- and CD8- double negative (DN) iNKT cells and incident CE, with an odds ratio of 0.62 [95% confidence interval (CI) 0.38-0.99; P = 0.046] comparing the highest vs. the lowest tertile of DN iNKT cells. The association remained significant after adjustment for cardiovascular risk factors with an odds ratio of 0.57 (95% CI 0.33-0.99; P = 0.046). In contrast, total iNKT cells were not significantly associated with incident CE after adjustment, with an odds ratio of 0.74 (95% CI 0.43-1.27; P = 0.276). Conclusion: Our findings indicate that animal studies suggesting an atherosclerosis-promoting role for iNKT cells may not translate to human cardiovascular disease as our data show an association between high circulating numbers of DN iNKT cells and decreased risk of incident CE.

Genetic Predisposition to Elevated Levels of Circulating ADAM17 Is Associated with the Risk of Severe COVID-19.

High levels of ADAM17 activity have emerged as an important mediator in severe COVID-19. This study aims to characterize eventual causal relationships between ADAM17 and COVID-19. Using Mendelian randomization analyses, we examined the causal effects of circulating ADAM17 on COVID-19 outcomes using summary statistics from large, genome-wide association studies of ADAM17 (up to 35,559 individuals) from the Icelandic Cancer Project and deCODE genetics, as well as critically ill COVID-19 patients (cases: 13,769; controls: 1,072,442), hospitalized COVID-19 patients (cases: 32,519; controls: 2,062,805) and reported SARS-CoV-2 infections (cases: 122,616; controls: 2,475,240) from the COVID-19 Host Genetics Initiative. The Mendelian randomization (MR) analyses demonstrated that a 1 standard deviation increase in genetically determined circulating ADAM17 (extracellular domain) was associated with an increased risk of developing critical ill COVID-19 (odds ratio [OR] = 1.26, 95% confidence interval [CI]:1.03-1.55). The multivariable MR analysis suggested a direct causal role of circulating ADAM17 (extracellular domain) in the risk of developing critical COVID-19 (OR = 1.09; 95% CI:1.01-1.17) when accounting for body mass index. No causal effect for the cytoplasmic domain of ADAM17 on COVID-19 was observed. Our results suggest that an increased genetic susceptibility to elevated levels of circulating ADAM17 (extracellular domain) is associated with a higher risk of suffering from severe COVID-19, strengthening the idea that the timely selective inhibition of ADAM17 could be a potential therapeutic target worthy of investigation.

Task Force for a rapid response to an outbreak of severe acute hepatitis of unknown aetiology in children in Portugal in 2022.

On 5 April 2022, the United Kingdom reported an increase of cases of severe acute hepatitis of unknown aetiology in children, several needing hospitalisation and some required liver transplant or died. Thereafter, 35 countries reported probable cases, almost half of them in Europe. Facing the alert, on 28 April, Portugal created a multidisciplinary Task Force (TF) for rapid detection of probable cases and response. The experts of the TF came from various disciplines: clinicians, laboratory experts, epidemiologists, public health experts and national and international communication. Moreover, Portugal adopted the European Centre for Disease Prevention and Control (ECDC) and the World Health Organization (WHO) case definition and recommendations. By 31 December 2022, 28 probable cases of severe acute hepatitis of unknown aetiology were reported: 16 male and 17 aged under 2 years. Of these cases, 23 were hospitalised but none required liver transplant or died. Adenovirus was detected from nine of 26 tested cases. No association was observed between adenovirus infection and hospital admission after adjusting for age, sex and region in a binomial regression model. The TF in Portugal may have contributed to increase awareness among clinicians, enabling early detection and prompt management of the outbreak.

Circulating soluble IL-6 receptor associates with plaque inflammation but not with atherosclerosis severity and cardiovascular risk.

BACKGROUND: The residual cardiovascular risk in subjects receiving guideline-recommended therapy is related to persistent vascular inflammation and IL-6 represents a target for its treatment. IL-6 binds to receptors on leukocytes and hepatocytes and/or by forming complexes with soluble IL-6 receptors (sIL-6R) binding to gp130 which is present on all cells. Here we aimed to estimate the associations of these two pathways with risk of cardiovascular disease (CVD). METHODS: IL-6 and sIL-6R were analyzed using the proximity extension assay. Baseline plasma samples were obtained from participants in the prospective Malmö Diet and Cancer (MDC) study (n = 4661), the SUMMIT VIP study (n = 1438) and the Carotid Plaque Imaging Project (CPIP, n = 285). Incident clinical events were obtained through national registers. Plaques removed at surgery were analyzed by immunohistochemistry and biochemical methods. RESULTS: During 23.1 ± 7.0 years follow-up, 575 subjects in the MDC cohort suffered a first myocardial infarction. Subjects in the highest tertile of IL-6 had an increased risk compared to the lowest tertile (HR and 95% CI 2.60 [2.08-3.25]). High plasma IL-6 was also associated with more atherosclerosis, increased arterial stiffness, and impaired endothelial function in SUMMIT VIP, but IL-6 was only weakly associated with plaque inflammation in CPIP. sIL-6R showed no independent association with risk of myocardial infarction, atherosclerosis severity or vascular function, but was associated with plaque inflammation. CONCLUSIONS: Our findings show that sIL-6R is a poor marker of CVD risk and associated vascular changes. However, the observation that sIL-6R reflects plaque inflammation highlights the complexity of the role of IL-6 in CVD.

Spatial Transcriptional Mapping Reveals Site-Specific Pathways Underlying Human Atherosclerotic Plaque Rupture.

BACKGROUND: Atherosclerotic plaque ruptures, triggered by blood flow-associated biomechanical forces, cause most myocardial infarctions and strokes. OBJECTIVES: This study aims to investigate the exact location and underlying mechanisms of atherosclerotic plaque ruptures, identifying therapeutic targets against cardiovascular events. METHODS: Histology, electron microscopy, bulk and spatial RNA sequencing on human carotid plaques were studied in proximal, most stenotic, and distal regions along the longitudinal blood flow direction. Genome-wide association studies were used to examine heritability enrichment and causal relationships of atherosclerosis and stroke. Associations between top differentially expressed genes (DEGs) and preoperative and postoperative cardiovascular events were examined in a validation cohort. RESULTS: In human carotid atherosclerotic plaques, ruptures predominantly occurred in the proximal and most stenotic regions but not in the distal region. Histologic and electron microscopic examination showed that proximal and most stenotic regions exhibited features of plaque vulnerability and thrombosis. RNA sequencing identified DEGs distinguishing the proximal and most stenotic regions from the distal region which were deemed as most relevant to atherosclerosis-associated diseases as shown by heritability enrichment analyses. The identified pathways associated with the proximal rupture-prone regions were validated by spatial transcriptomics, firstly in human atherosclerosis. Of the 3 top DEGs, matrix metallopeptidase 9 emerged particularly because Mendelian randomization suggested that its high circulating levels were causally associated with atherosclerosis risk. CONCLUSIONS: Our findings show plaque site-specific transcriptional signatures associated with proximal rupture-prone regions of carotid atherosclerotic plaques. This led to the geographical mapping of novel therapeutic targets, such as matrix metallopeptidase 9, against plaque rupture.