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Caristo Diagnostics, an Oxford University spinout company, has been launched to commercialise a new coronary CT image analysis technology that can flag patients at risk of deadly heart attacks years before they occur.
Relationship between left ventricular shape and cardiovascular risk factors: comparison between the Multi-Ethnic Study of Atherosclerosis and UK Biobank.
BACKGROUND: Statistical shape atlases have been used in large-cohort studies to investigate relationships between heart shape and risk factors. The generalisability of these relationships between cohorts is unknown. The aims of this study were to compare left ventricular (LV) shapes in patients with differing cardiovascular risk factor profiles from two cohorts and to investigate whether LV shape scores generated with respect to a reference cohort can be directly used to study shape differences in another cohort. METHODS: Two cardiac MRI cohorts were included: 2106 participants (median age: 65 years, 54% women) from the Multi-Ethnic Study of Atherosclerosis (MESA) and 2960 participants (median age: 64 years, 52% women) from the UK Biobank (UKB) study. LV shape atlases were constructed from 3D LV models derived from expert-drawn contours from separate core labs. Atlases were considered generalisable for a risk factor if the area under the receiver operating characteristic curves (AUC) were not significantly different (p>0.05) between internal (within-cohort) and external (cross-cohort) cases. RESULTS: LV mass and volume indices were differed significantly between cohorts, even in age-matched and sex-matched cases without risk factors, partly reflecting different core lab analysis protocols. For the UKB atlas, internal and external discriminative performance were not significantly different for hypertension (AUC: 0.77 vs 0.76, p=0.37), diabetes (AUC: 0.79 vs 0.77, p=0.48), hypercholesterolaemia (AUC: 0.76 vs 0.79, p=0.38) and smoking (AUC: 0.69 vs 0.67, p=0.18). For the MESA atlas, diabetes (AUC: 0.79 vs 0.74, p=0.09) and hypercholesterolaemia (AUC: 0.75 vs 0.70, p=0.10) were not significantly different. Both atlases showed significant differences for obesity. CONCLUSIONS: The MESA and UKB atlases demonstrated good generalisability for diabetes and hypercholesterolaemia, without requiring corrections for differences in mass and volume. Significant differences in obesity may be due to different relationships between obesity and heart shapes between cohorts.
Traversing the drug discovery landscape using native mass spectrometry.
As health needs in our society evolve, the field of drug discovery must undergo constant innovation and improvement to identify novel targets and drug candidates. Owing to its ability to simultaneously capture biological interactions and provide in-depth molecular characterisation of the species involved, native mass spectrometry is starting to play an important role in this endeavour. Here, we discuss recent contributions that native mass spectrometry has made to drug discovery including deciphering protein-small molecule interactions, unravelling biochemical pathways, and integrating with complementary structural approaches.
Role of primary and secondary care data in atrial fibrillation ascertainment: impact on risk factor associations, patient management, and mortality in UK Biobank.
AIMS: Electronic healthcare records (EHR) are at the forefront of advances in epidemiological research emerging from large-scale population biobanks and clinical studies. Hospital admissions, diagnoses, and procedures (HADP) data are often used to identify disease cases. However, this may result in incomplete ascertainment of chronic conditions such as atrial fibrillation (AF), which are principally managed in primary care (PC). We examined the relevance of EHR sources for AF ascertainment, and the implications for risk factor associations, patient management, and outcomes in UK Biobank. METHODS AND RESULTS: UK Biobank is a prospective study, with HADP and PC records available for 230 000 participants (to 2016). AF cases were ascertained in three groups: from PC records only (PC-only), HADP only (HADP-only), or both (PC + HADP). Conventional statistical methods were used to describe differences between groups in terms of characteristics, risk factor associations, ascertainment timing, rates of anticoagulation, and post-AF stroke and death. A total of 7136 incident AF cases were identified during 7 years median follow-up (PC-only: 22%, PC + HADP: 49%, HADP-only: 29%). There was a median lag of 1.3 years between cases ascertained in PC and subsequently in HADP. AF cases in each of the ascertainment groups had comparable baseline demographic characteristics. However, AF cases identified in hospital data alone had a higher prevalence of cardiometabolic comorbidities and lower rates of subsequent anticoagulation (PC-only: 44%, PC + HADP: 48%, HADP-only: 10%, P < 0.0001) than other groups. HADP-only cases also had higher rates of death [PC-only: 9.3 (6.8, 12.7), PC + HADP: 23.4 (20.5, 26.6), HADP-only: 81.2 (73.8, 89.2) events per 1000 person-years, P < 0.0001] compared to other groups. CONCLUSION: Integration of data from primary care with that from hospital records has a substantial impact on AF ascertainment, identifying a third more cases than hospital records alone. However, about a third of AF cases recorded in hospital were not present in the primary care records, and these cases had lower rates of anticoagulation, as well as higher mortality from both cardiovascular and non-cardiovascular causes. Initiatives aimed at enhancing information exchange of clinically confirmed AF between healthcare settings have the potential to benefit patient management and AF-related outcomes at an individual and population level. This research underscores the importance of access and integration of de-identified comprehensive EHR data for a definitive understanding of patient trajectories, and for robust epidemiological and translational research into AF.
Cardiovascular Magnetic Resonance Before Invasive Coronary Angiography in Suspected Non-ST-Segment Elevation Myocardial Infarction.
BACKGROUND: In suspected non-ST-segment elevation myocardial infarction (NSTEMI), this presumed diagnosis may not hold true in all cases, particularly in patients with nonobstructive coronary arteries (NOCA). Additionally, in multivessel coronary artery disease, the presumed infarct-related artery may be incorrect. OBJECTIVES: This study sought to assess the diagnostic utility of cardiac magnetic resonance (CMR) before invasive coronary angiogram (ICA) in suspected NSTEMI. METHODS: A total of 100 consecutive stable patients with suspected acute NSTEMI (70% male, age 62 ± 11 years) prospectively underwent CMR pre-ICA to assess cardiac function (cine), edema (T2-weighted imaging, T1 mapping), and necrosis/scar (late gadolinium enhancement). CMR images were interpreted blinded to ICA findings. The clinical care and ICA teams were blinded to CMR findings until post-ICA. RESULTS: Early CMR (median 33 hours postadmission and 4 hours pre-ICA) confirmed only 52% (52 of 100) of patients had subendocardial infarction, 15% transmural infarction, 18% nonischemic pathologies (myocarditis, takotsubo, and other forms of cardiomyopathies), and 11% normal CMR; 4% were nondiagnostic. Subanalyses according to ICA findings showed that, in patients with obstructive coronary artery disease (73 of 100), CMR confirmed only 84% (61 of 73) had MI, 10% (7 of 73) nonischemic pathologies, and 5% (4 of 73) normal. In patients with NOCA (27 of 100), CMR found MI in only 22% (6 of 27 true MI with NOCA), and reclassified the presumed diagnosis of NSTEMI in 67% (18 of 27: 11 nonischemic pathologies, 7 normal). In patients with CMR-MI and obstructive coronary artery disease (61 of 100), CMR identified a different infarct-related artery in 11% (7 of 61). CONCLUSIONS: In patients presenting with suspected NSTEMI, a CMR-first strategy identified MI in 67%, nonischemic pathologies in 18%, and normal findings in 11%. Accordingly, CMR has the potential to affect at least 50% of all patients by reclassifying their diagnosis or altering their potential management.
Evaluating the transcriptional regulators of arterial gene expression via a catalogue of characterized arterial enhancers.
The establishment and growth of the arterial endothelium requires the coordinated expression of numerous genes. However, regulation of this process is not yet fully understood. Here, we combined in silico analysis with transgenic mice and zebrafish models to characterize arterial-specific enhancers associated with eight key arterial identity genes (Acvrl1/Alk1, Cxcr4, Cxcl12, Efnb2, Gja4/Cx37, Gja5/Cx40, Nrp1 and Unc5b). Next, to elucidate the regulatory pathways upstream of arterial gene transcription, we investigated the transcription factors binding each arterial enhancer compared to a similar assessment of non-arterial endothelial enhancers. These results found that binding of SOXF and ETS factors was a common occurrence at both arterial and pan-endothelial enhancers, suggesting neither are sufficient to direct arterial specificity. Conversely, FOX motifs independent of ETS motifs were over-represented at arterial enhancers. Further, MEF2 and RBPJ binding was enriched but not ubiquitous at arterial enhancers, potentially linked to specific patterns of behaviour within the arterial endothelium. Lastly, there was no shared or arterial-specific signature for WNT-associated TCF/LEF, TGFβ/BMP-associated SMAD1/5 and SMAD2/3, shear stress-associated KLF4 or venous-enriched NR2F2. This cohort of well characterized and in vivo-verified enhancers can now provide a platform for future studies into the interaction of different transcriptional and signalling pathways with arterial gene expression.
Pharmacological profiling of small molecule modulators of the TMEM16A channel and their implications for the control of artery and capillary function.
BACKGROUND AND PURPOSE: TMEM16A chloride channels constitute a depolarising mechanism in arterial smooth muscle cells (SMCs) and contractile cerebral pericytes. TMEM16A pharmacology is incompletely defined. We elucidated the mode of action and selectivity of a recently identified positive allosteric modulator of TMEM16A (PAM_16A) and of a range of TMEM16A inhibitors. We also explore the consequences of selective modulation of TMEM16A activity on arterial and capillary function. EXPERIMENTAL APPROACH: Patch-clamp electrophysiology, isometric tension recordings, live imaging of cerebral cortical capillaries and assessment of cell death were employed to explore the effect of selective pharmacological control of TMEM16A on vascular function. KEY RESULTS: In low intracellular free Ca2+ concentrations ([Ca2+]i), nanomolar concentrations of PAM_16A activated heterologous TMEM16A channels, while being almost ineffective on the closely related TMEM16B channel. In either the absence of Ca2+ or in saturating [Ca2+]i, PAM_16A had no effect on TMEM16A currents at physiological potentials. PAM_16A selectively activated TMEM16A currents in SMCs and enhanced aortic contraction caused by phenylephrine or angiotensin-II and capillary (pericyte) constriction evoked by endothelin-1 or oxygen-glucose deprivation (OGD) to simulate cerebral ischaemia. Conversely, selective TMEM16A inhibition with Ani9 facilitated aortic, mesenteric and pericyte relaxation, and protected against OGD-mediated pericyte cell death. Unlike PAM_16A and Ani9, a range of other available modulators were found to interfere with endogenous cationic currents in SMCs. CONCLUSIONS AND IMPLICATIONS: Arterial tone and capillary diameter can be controlled with TMEM16A modulators, highlighting TMEM16A as a target for disorders with a vascular component, including hypertension, stroke, Alzheimer's disease and vascular dementia.
Multiomic analyses direct hypotheses for Creutzfeldt-Jakob disease risk genes.
Prions are assemblies of misfolded prion protein that cause several fatal and transmissible neurodegenerative diseases, with the most common phenotype in humans being sporadic Creutzfeldt-Jakob disease (sCJD). Aside from variation of the prion protein itself, molecular risk factors are not well understood. Prion and prion-like mechanisms are thought to underpin common neurodegenerative disorders meaning that the elucidation of mechanisms could have broad relevance. Herein we sought to further develop our understanding of the factors that confer risk of sCJD using a systematic gene prioritization and functional interpretation pipeline based on multiomic integrative analyses. We integrated the published sCJD genome-wide association study (GWAS) summary statistics with publicly available bulk brain and brain cell type gene and protein expression datasets. We performed multiple transcriptome and proteome-wide association studies (TWAS & PWAS) and Bayesian genetic colocalization analyses between sCJD risk association signals and multiple brain molecular quantitative trait loci signals. We then applied our systematic gene prioritization pipeline on the obtained results and nominated prioritized sCJD risk genes with risk-associated molecular mechanisms in a transcriptome and proteome-wide manner. Genetic upregulation of both gene and protein expression of syntaxin-6 (STX6) in the brain was associated with sCJD risk in multiple datasets, with a risk-associated gene expression regulation specific to oligodendrocytes. Similarly, increased gene and protein expression of protein disulfide isomerase family A member 4 (PDIA4), involved in the unfolded protein response, was linked to increased disease risk, particularly in excitatory neurons. Protein expression of mesencephalic astrocyte derived neurotrophic factor (MANF), involved in protection against endoplasmic reticulum stress and sulfatide binding (linking to the enzyme in the final step of sulfatide synthesis, encoded by sCJD risk gene GAL3ST1), was identified as protective against sCJD. In total 32 genes were prioritized into two tiers based on the level of evidence and confidence for further studies. This study provides insights into the genetically-associated molecular mechanisms underlying sCJD susceptibility and prioritizes several specific hypotheses for exploration beyond the prion protein itself and beyond the previously highlighted sCJD risk loci through the newly prioritized sCJD risk genes and mechanisms. These findings highlight the importance of glial cells, sulfatides and the excitatory neuron unfolded protein response in sCJD pathogenesis.
Genome-wide association analyses identify distinct genetic architectures for age-related macular degeneration across ancestries.
To effectively reduce vision loss due to age-related macular generation (AMD) on a global scale, knowledge of its genetic architecture in diverse populations is necessary. A critical element, AMD risk profiles in African and Hispanic/Latino ancestries, remains largely unknown. We combined data in the Million Veteran Program with five other cohorts to conduct the first multi-ancestry genome-wide association study of AMD and discovered 63 loci (30 novel). We observe marked cross-ancestry heterogeneity at major risk loci, especially in African-ancestry populations which demonstrate a primary signal in a major histocompatibility complex class II haplotype and reduced risk at the established CFH and ARMS2/HTRA1 loci. Dissecting local ancestry in admixed individuals, we find significantly smaller marginal effect sizes for CFH risk alleles in African ancestry haplotypes. Broadening efforts to include ancestrally distinct populations helped uncover genes and pathways that boost risk in an ancestry-dependent manner and are potential targets for corrective therapies.
Integration of genetic testing into diagnostic pathways for cardiomyopathies: a clinical consensus statement by the ESC Council on Cardiovascular Genomics.
In the modern era, cardiologists managing patients and families with cardiomyopathies need to be familiar with every stage of the diagnostic pathway from clinical phenotyping to the prescription and interpretation of genetic tests. This clinical consensus statement from the ESC Council for Cardiovascular Genomics aims to promote the integration of genetic testing into routine cardiac care of patients with cardiomyopathies, as recommended in the 2023 ESC guidelines for cardiomyopathies. The document describes the types of genetic tests currently available and provides advice on their prescription and for counselling after the return of genetic findings, including the approach in patients and families with variants of unknown significance.
Genome-wide association neural networks identify genes linked to family history of Alzheimer's disease.
Augmenting traditional genome-wide association studies (GWAS) with advanced machine learning algorithms can allow the detection of novel signals in available cohorts. We introduce "genome-wide association neural networks (GWANN)" a novel approach that uses neural networks (NNs) to perform a gene-level association study with family history of Alzheimer's disease (AD). In UK Biobank, we defined cases (n = 42 110) as those with AD or family history of AD and sampled an equal number of controls. The data was split into an 80:20 ratio of training and testing samples, and GWANN was trained on the former followed by identifying associated genes using its performance on the latter. Our method identified 18 genes to be associated with family history of AD. APOE, BIN1, SORL1, ADAM10, APH1B, and SPI1 have been identified by previous AD GWAS. Among the 12 new genes, PCDH9, NRG3, ROR1, LINGO2, SMYD3, and LRRC7 have been associated with neurofibrillary tangles or phosphorylated tau in previous studies. Furthermore, there is evidence for differential transcriptomic or proteomic expression between AD and healthy brains for 10 of the 12 new genes. A series of post hoc analyses resulted in a significantly enriched protein-protein interaction network (P-value
Genetic epidemiology of Alzheimer's disease
Dementia is a major health problem in the elderly. It is a syndrome characterized by impairment in intellectual functioning resulting in a distressing condition both for the patient and caregiver. Alzheimer's disease (AD) is the most common cause of dementia in Western society. AD is clinically characterized by an insidous onset of decline in memory and at least one other area of cognition. Additional characteristics are a gradually progressive course, a preserved level of consciousness, and absence of other conditions able to cause these symptoms. The pathological hallmark in brains of AD patients are extracellular plaques composed mainly of the amyloid-p peptide and intracellular neurofibrillary tangles containing hyperphosphorylated tau protein (Braak and Braak, 1991).
Leucocyte telomere length and conduction system ageing.
BACKGROUND: Deterioration of the cardiac conduction system is an important manifestation of cardiac ageing. Cellular ageing is accompanied by telomere shortening and telomere length (TL) is often regarded as a marker of biological ageing, potentially adding information regarding conduction disease over and above chronological age. We therefore sought to evaluate the association between leucocyte telomere length (LTL) on two related, but distinct aspects of the cardiac conduction system: ECG measures of conduction (PR interval and QRS duration) and incident pacemaker implantation in a large population-based cohort. METHODS: In the UK Biobank, we measured PR interval and QRS duration from signal-averaged ECG waveforms in 59 868 and 62 266 participants, respectively. Incident pacemaker implantation was ascertained using hospital episode data from 420 071 participants. Associations with LTL were evaluated in (Cox) multivariable regression analyses adjusted for potential confounders. Putative causal effects of LTL were investigated by mendelian randomisation (MR). RESULTS: Mean PR interval and QRS duration were 144.2 ms (± 20.4) and 92.3 ms (± 7.8), respectively, and there were 7169 (1.7%) incident pacemaker implantations, during a median follow-up period of 13.6 (IQR 1.5) years. LTL was significantly associated with PR interval (0.19 ms (95% CI: 0.03 to 0.35), per 1 SD shorter LTL, p=0.021), but not QRS duration. After adjusting for age, sex and cardiovascular risk factors, shorter LTL remained associated with an increased risk for incident pacemaker implantation (HR per SD decrease in LTL: 1.03 (95% CI: 1.01 to 1.06), p=0.012). MR analysis showed a trend towards an association of shorter LTL with longer PR interval and higher risk of pacemaker implantation but was likely to be underpowered. CONCLUSIONS: Shorter LTL was significantly, and possibly causally, associated with prolongation of atrioventricular conduction and pacemaker implantation, independent of traditional cardiovascular risk factors. Our findings support further research to explore the role of ageing on cardiac conduction beyond chronological age.
Associations of accelerometer-measured physical activity, sedentary behaviour, and sleep with next-day cognitive performance in older adults: a micro-longitudinal study.
BACKGROUND: Previous studies suggest short-term cognitive benefits of physical activity occurring minutes to hours after exercise. Whether these benefits persist the following day and the role of sleep is unclear. We examined associations of accelerometer-assessed physical activity, sedentary behaviour, and sleep with next-day cognitive performance in older adults. METHODS: British adults aged 50-83 years (N = 76) without evidence of cognitive impairment or dementia wore accelerometers for eight days, and took daily cognitive tests of attention, memory, psychomotor speed, executive function, and processing speed. Physical behaviour (time spent in moderate-to-vigorous physical activity [MVPA], light physical activity [LPA], and sedentary behaviour [SB]) and sleep characteristics (overnight sleep duration, time spent in rapid eye movement [REM] sleep and slow wave sleep [SWS]) were extracted from accelerometers, with sleep stages derived using a novel polysomnography-validated machine learning algorithm. We used linear mixed models to examine associations of physical activity and sleep with next-day cognitive performance, after accounting for habitual physical activity and sleep patterns during the study period and other temporal and contextual factors. RESULTS: An additional 30 min of MVPA on the previous day was associated with episodic memory scores 0.15 standard deviations (SD; 95% confidence interval = 0.01 to 0.29; p = 0.03) higher and working memory scores 0.16 SD (0.03 to 0.28; p = 0.01) higher. Each 30-min increase in SB was associated with working memory scores 0.05 SD (0.00 to 0.09) lower (p = 0.03); adjustment for sleep characteristics on the previous night did not substantively change these results. Independent of MVPA on the previous day, sleep duration ≥ 6 h (compared with
Halving premature death and improving quality of life at all ages: cross-country analyses of past trends and future directions.
BACKGROUND: Although death in old age is unavoidable, premature death-defined here as death before age 70 years-is not. To assess whether halving premature mortality by 2050 is feasible, we examined the large variation in premature death rates before age 70 years and trends over the past 50 years (1970-2019), covering ten world regions and the 30 most-populous nations. This analysis was undertaken in conjunction with the third report of The Lancet Commission on Investing in Health: Global Health 2050: the path to halving premature death by mid-century. METHODS: In this cross-country analysis of past mortality trends and future directions, all analyses on the probability of premature death (PPD) were conducted using life tables from the UN World Population Prospects 2024. For each sex, country, and year, probability of death was calculated from these life tables with 1-year age-specific mortality rates. FINDINGS: Globally, PPD decreased from 56% in 1970 to 31% in 2019, although some countries saw reversals because of conflict, social instability, or HIV and AIDS. Child mortality has decreased faster than adult mortality. Among all countries, 34 halved their PPD over three decades between 1970 and 2019. Among the 30 most-populous countries, seven countries, with varying levels of baseline PPD and income, halved their PPD in the past half century. Seven of the most-populous countries had average annual rates of improvement in the period 2010-19 that, if sustained, could lead to a halving of PPD by 2050, including Korea (3·9%), Bangladesh (2·8%), Russia (2·7%), Ethiopia (2·4%), Iran (2·4%), South Africa (2·4%), and Türkiye (2·3%). INTERPRETATION: Halving premature death by 2050 is feasible, although substantial investments in child and adult health are needed to sustain or accelerate the rate of improvement for high-performing and medium-performing countries. Particular attention must be paid to countries with very low or a worsening rate of improvement in PPD. By reducing premature mortality, more people will live longer and more healthy lives. However, as people live longer, the absolute number of years lived with chronic disease will increase and investments in services reducing chronic disease morbidity are needed. FUNDING: The Norwegian Agency for Development Cooperation, the Bill & Melinda Gates Foundation, and a Norwegian Research Council Centre of Excellence grant.
Lateral Atrial Expression Patterns Provide Insights into Local Transcription Disequilibrium Contributing to Disease Susceptibility.
BACKGROUND: Transcriptional dysregulation, possibly affected by genetic variation, contributes to disease development. Due to dissimilarities in development, function, and remodeling during disease progression, transcriptional differences between the left atrial (LA) and right atrial (RA) may provide insight into diseases such as atrial fibrillation. METHODS: Lateral differences in atrial transcription were evaluated in CATCH ME (Characterizing Atrial fibrillation by Translating its Causes into Health Modifiers in the Elderly) using a 2-stage discovery and replication design. The design took advantage of the availability of 32 paired samples, for which both LA and RA tissue were obtained, as a discovery cohort, and 98 LA and 69 RA unpaired samples utilized as a replication cohort. RESULTS: A total of 714 transcripts were identified and replicated as differentially expressed (DE) between LA and RA, as well as 98 exons in 55 genes. Approximately 50% of DE transcripts were colocated with another frequently correlated DE transcript (PFDR ≤0.05 for 579 regions). These transcription disequilibrium blocks contained examples including side-specific differential exon usage, such as the PITX2 locus, where ENPEP showed evidence of differential exon usage. Analysis of this region in conjunction with BMP10 identified rs9790621 as associated with ENPEP transcription in LA, while rs7687878 was associated with BMP10 expression in RA. In RA, BMP10 and ENPEP were strongly correlated in noncarriers, which was attenuated in risk-allele carriers, where BMP10 and PITX2 expression were strongly correlated. CONCLUSIONS: These results significantly expand knowledge of the intricate, tissue-specific transcriptional landscape in human atria, including DE transcripts and side-specific isoform expression. Furthermore, they suggest the existence of blocks of transcription disequilibrium influenced by genetics.