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Mechanisms of ischaemia-induced arrhythmias in hypertrophic cardiomyopathy: a large-scale computational study.
AIMS: Lethal arrhythmias in hypertrophic cardiomyopathy (HCM) are widely attributed to myocardial ischaemia and fibrosis. How these factors modulate arrhythmic risk remains largely unknown, especially as invasive mapping protocols are not routinely used in these patients. By leveraging multiscale digital-twin technologies, we aim to investigate ischaemic mechanisms of increased arrhythmic risk in HCM. METHODS AND RESULTS: Computational models of human HCM cardiomyocytes, tissue and ventricles were used to simulate outcomes of phase 1A acute myocardial ischaemia. Cellular response predictions were validated with patch-clamp studies of human HCM cardiomyocytes (n=12 cells, N=5 patients). Ventricular simulations were informed by typical distributions of subendocardial/transmural ischaemia as analysed in perfusion scans (N=28 patients). S1-S2 pacing protocols were used to quantify arrhythmic risk for scenarios in which regions of septal obstructive hypertrophy were affected by (i) ischaemia, (ii) ischaemia and impaired repolarisation, and (iii) ischaemia, impaired repolarisation, and diffuse fibrosis.HCM cardiomyocytes exhibited enhanced action potential and abnormal effective refractory period shortening to ischaemic insults. Analysis of c.a. 75,000 re-entry induction cases revealed that the abnormal HCM cellular response enabled establishment of arrhythmia at milder ischaemia than otherwise possible in healthy myocardium, due to larger refractoriness gradients that promoted conduction block. Arrhythmias were more easily sustained in transmural than subendocardial ischaemia. Mechanisms of ischaemia-fibrosis interaction were strongly electrophysiology dependent. Fibrosis enabled asymmetric re-entry patterns and break-up into sustained ventricular tachycardia. CONCLUSIONS: HCM ventricles exhibited an increased risk to non-sustained and sustained re-entry, largely dominated by an impaired cellular response and deleterious interactions with the diffuse fibrotic substrate.
Phage defence system CBASS is regulated by a prokaryotic E2 enzyme that imitates the ubiquitin pathway.
The cyclic-oligonucleotide-based anti-phage signalling system (CBASS) is a type of innate prokaryotic immune system. Composed of a cyclic GMP-AMP synthase (cGAS) and CBASS-associated proteins, CBASS uses cyclic oligonucleotides to activate antiviral immunity. One major class of CBASS contains a homologue of eukaryotic ubiquitin-conjugating enzymes, which is either an E1-E2 fusion or a single E2. However, the functions of single E2s in CBASS remain elusive. Here, using biochemical, genetic, cryo-electron microscopy and mass spectrometry investigations, we discover that the E2 enzyme from Serratia marcescens regulates cGAS by imitating the ubiquitination cascade. This includes the processing of the cGAS C terminus, conjugation of cGAS to a cysteine residue, ligation of cGAS to a lysine residue, cleavage of the isopeptide bond and poly-cGASylation. The poly-cGASylation activates cGAS to produce cGAMP, which acts as an antiviral signal and leads to cell death. Thus, our findings reveal a unique regulatory role of E2 in CBASS.
Associations of traditional cardiovascular risk factors with 15-year blood pressure change and trajectories in Chinese adults: a prospective cohort study.
OBJECTIVE: How traditional cardiovascular disease (CVD) risk factors are related to long-term blood pressure change (BPC) or trajectories remain unclear. We aimed to examine the independent associations of these factors with 15-year BPC and trajectories in Chinese adults. METHODS: We included 15 985 participants who had attended three surveys, including 2004-2008 baseline survey, and 2013-2014 and 2020-2021 resurveys, over 15 years in the China Kadoorie Biobank (CKB). We measured systolic and diastolic blood pressure (SBP and DBP), height, weight, and waist circumference (WC). We asked about the sociodemographic characteristics and lifestyle factors, including smoking, alcohol drinking, intake of fresh vegetables, fruits, and red meat, and physical activity, using a structured questionnaire. We calculated standard deviation (SD), cumulative blood pressure (cumBP), coefficient of variation (CV), and average real variability (ARV) as long-term BPC proxies. We identified blood pressure trajectories using the latent class growth model. RESULTS: Most baseline sociodemographic and lifestyle characteristics were associated with cumBP. After adjusting for other characteristics, the cumSBP (mmHg × year) increased by 116.9 [95% confidence interval (CI): 111.0, 122.7] for every 10 years of age. The differences of cumSBP in heavy drinkers of ≥60 g pure alcohol per day and former drinkers were 86.7 (60.7, 112.6) and 48.9 (23.1, 74.8) compared with less than weekly drinkers. The cumSBP in participants who ate red meat less than weekly was 29.4 (12.0, 46.8) higher than those who ate red meat daily. The corresponding differences of cumSBP were 127.8 (120.7, 134.9) and 70.2 (65.0, 75.3) for BMI per 5 kg/m2 and WC per 10 cm. Most of the findings of other BPC measures by baseline characteristics were similar to the cumBP, but the differences between groups were somewhat weaker. Alcohol drinking was associated with several high-risk trajectories of SBP and DBP. Both BMI and WC were independently associated with all high-risk blood pressure trajectories. CONCLUSIONS: Several traditional CVD risk factors were associated with unfavorable long-term BPC or blood pressure trajectories in Chinese adults.
Predictive value of 8-year blood pressure measures in intracerebral hemorrhage risk over 5 years.
AIMS: The relationships between long-term blood pressure (BP) measures and intracerebral hemorrhage (ICH), as well as their predictive ability on ICH, were unclear. We aimed to investigate the independent associations of multiple BP measures with subsequent 5-year ICH risk, as well as the incremental value of these measures over a single-point BP measurement in ICH risk prediction. METHODS: We included 12,398 participants from the China Kadoorie Biobank (CKB) who completed three surveys every four to five years. The following long-term BP measures were calculated: mean, minimum, maximum, standard deviation, coefficient of variation, average real variability, and cumulative BP exposure (cumBP). Cox proportional hazard models were used to examine the associations between these measures and ICH. The potential incremental value of these measures in ICH risk prediction was assessed using Harrell's C statistics, continuous net reclassification improvement (cNRI), and relative integrated discrimination improvement (rIDI). RESULTS: The hazard ratios (95% confidence intervals) of incident ICH associated with per SD increase in cumSBP and cumDBP were 1.62 (1.25, 2.10) and 1.59 (1.23, 2.07), respectively. When cumBP was added to the conventional 5-year ICH risk prediction model, the C-statistic change was 0.009 (-0.001, 0.019), the cNRI was 0.267 (0.070, 0.464), and the rIDI was 18.2% (5.8%, 30.7%). Further subgroup analyses revealed a consistent increase in cNRI and rIDI in men, rural residents, and participants without diabetes. Other long-term BP measures showed no statistically significant associations with incident ICH and generally did not improve model performance. CONCLUSION: The nearly 10-year cumBP was positively associated with an increased 5-year risk of ICH and could significantly improve risk reclassification for the ICH risk prediction model that included single-point BP measurement.
Development and validation of a new algorithm for improved cardiovascular risk prediction
QRISK algorithms use data from millions of people to help clinicians identify individuals at high risk of cardiovascular disease (CVD). Here, we derive and externally validate a new algorithm, which we have named QR4, that incorporates novel risk factors to estimate 10-year CVD risk separately for men and women. Health data from 9.98 million and 6.79 million adults from the United Kingdom were used for derivation and validation of the algorithm, respectively. Cause-specific Cox models were used to develop models to predict CVD risk, and the performance of QR4 was compared with version 3 of QRISK, Systematic Coronary Risk Evaluation 2 (SCORE2) and atherosclerotic cardiovascular disease (ASCVD) risk scores. We identified seven novel risk factors in models for both men and women (brain cancer, lung cancer, Down syndrome, blood cancer, chronic obstructive pulmonary disease, oral cancer and learning disability) and two additional novel risk factors in women (pre-eclampsia and postnatal depression). On external validation, QR4 had a higher C statistic than QRISK3 in both women (0.835 (95% confidence interval (CI), 0.833–0.837) and 0.831 (95% CI, 0.829–0.832) for QR4 and QRISK3, respectively) and men (0.814 (95% CI, 0.812–0.816) and 0.812 (95% CI, 0.810–0.814) for QR4 and QRISK3, respectively). QR4 was also more accurate than the ASCVD and SCORE2 risk scores in both men and women. The QR4 risk score identifies new risk groups and provides superior CVD risk prediction in the United Kingdom compared with other international scoring systems for CVD risk.
Role of the Lymphatics in Cardiac Disease.
Cardiovascular diseases remain the largest cause of death worldwide with recent evidence increasingly attributing the development and progression of these diseases to an exacerbated inflammatory response. As a result, significant research is now focused on modifying the immune environment to prevent the disease progression. This in turn has highlighted the lymphatic system in the pathophysiology of cardiovascular diseases owing, in part, to its established function in immune cell surveillance and trafficking. In this review, we highlight the role of the cardiac lymphatic system and its potential as an immunomodulatory therapeutic target in selected cardiovascular diseases.
The effect of sodium-glucose cotransporter-2 inhibitors on inflammatory biomarkers: A meta-analysis of randomized controlled trials.
AIMS: To conduct a meta-analysis of randomized controlled trials (RCTs) to assess the effect of sodium-glucose cotransporter-2 (SGLT2) inhibitors on inflammatory biomarkers. METHODS: Medline, Embase and the Cochrane Library were searched for RCTs investigating the effect of SGLT2 inhibitors on inflammatory biomarkers, adipokine profiles and insulin sensitivity. RESULTS: Thirty-eight RCTs were included (14 967 participants, 63.3% male, mean age 62 ± 8.6 years) with a median (interquartile range) follow-up of 16 (12-24) weeks. Meta-analysis showed that SGLT2 inhibitors significantly improved adiponectin, interleukin-6, tumour necrosis factor receptor-1 (vs. placebo alone: standardized mean difference [SMD] 0.34 [95% confidence interval {CI} 0.23, 0.45], mean difference [MD] -0.85 pg/mL [95% CI -1.32, -0.38], SMD -0.13 [95% CI -0.20, -0.06], respectively), leptin and homeostatic model assessment of insulin resistance index (vs. CONTROL: SMD -0.20 [95% CI -0.33, -0.07], MD -0.83 [95% CI -1.32, -0.33], respectively). There were no significant changes in C-reactive protein (CRP), tumour necrosis factor-α, plasminogen activator inhibitor-1, fibroblast growth factor-21 or monocyte chemoattractant protein-1. CONCLUSIONS: Our analysis shows that SGLT2 inhibitors likely improve adipokine biomarkers and insulin sensitivity, but there is little evidence that SGLT2 inhibitors improve other inflammatory biomarkers including CRP.
Arrhythmogenesis in Fabry Disease.
PURPOSE OF REVIEW: Fabry Disease (FD) is a rare lysosomal storage disorder characterised by multiorgan accumulation of glycosphingolipid due to deficiency in the enzyme α-galactosidase A. Cardiac sphingolipid accumulation triggers various types of arrhythmias, predominantly ventricular arrhythmia, bradyarrhythmia, and atrial fibrillation. Arrhythmia is likely the primary contributor to FD mortality with sudden cardiac death, the most frequent cardiac mode of death. Traditionally FD was seen as a storage cardiomyopathy triggering left ventricular hypertrophy, diastolic dysfunction, and ultimately, systolic dysfunction in advanced disease. The purpose of this review is to outline the current evidence exploring novel mechanisms underlying the arrhythmia substrate. RECENT FINDINGS: There is growing evidence that FD cardiomyopathy is a primary arrhythmic disease with each stage of cardiomyopathy (accumulation, hypertrophy, inflammation, and fibrosis) contributing to the arrhythmia substrate via various intracellular, extracellular, and environmental mechanisms. It is therefore important to understand how these mechanisms contribute to an individual's risk of arrhythmia in FD. In this review, we outline the epidemiology of arrhythmia, pathophysiology of arrhythmogenesis, risk stratification, and cardiac therapy in FD. We explore how advances in conventional cardiac investigations performed in FD patients including 12-lead electrocardiography, transthoracic echocardiography, and cardiac magnetic resonance imaging have enabled early detection of pro-arrhythmic substrate. This has allowed for appropriate risk stratification of FD patients. This paves the way for future work exploring the development of therapeutic initiatives and risk prediction models to reduce the burden of arrhythmia.
Conducting umbrella reviews.
In this article, Lazaros Belbasis and colleagues explain the rationale for umbrella reviews and the key steps involved in conducting an umbrella review, using a working example.
Introduction to Epidemiological Studies.
The basic epidemiological study designs are cross-sectional, case-control, and cohort studies. Cross-sectional studies provide a snapshot of a population by determining both exposures and outcomes at one time point. Cohort studies identify the study groups based on the exposure and, then, the researchers follow up study participants to measure outcomes. Case-control studies identify the study groups based on the outcome, and the researchers retrospectively collect the exposure of interest. The present chapter discusses the basic concepts, the advantages, and disadvantages of epidemiological study designs and their systematic biases, including selection bias, information bias, and confounding.
Environmental Risk Factors and Amyotrophic Lateral Sclerosis: An Umbrella Review and Critical Assessment of Current Evidence from Systematic Reviews and Meta-Analyses of Observational Studies.
BACKGROUND: The pathogenesis of amyotrophic lateral sclerosis (ALS) involves both environmental and genetic factors. Our study aimed at summarising the environmental risk factors for ALS, assessing the evidence for diverse biases, and pinpointing risk factors with high epidemiological credibility. METHODS: We searched PubMed from inception to August 20, 2015, to identify systematic reviews and meta-analyses of observational studies examining associations between environmental factors and ALS. For each meta-analysis, we estimated the summary effect size by the use of random-effects and fixed-effects models, the 95% CI, the 95% prediction interval (PI), and the between-study heterogeneity. We assessed the evidence of small-study effects and excess significance bias. RESULTS: Sixteen unique meta-analyses of different risk factors and ALS were considered. Of them, 5 were statistically significant at p < 0.001 under the random-effects model. Only one factor presented robust evidence for a convincing association. This association pertained to chronic occupational exposure to lead (random-effects OR 1.81, 95% CI 1.39-2.35). CONCLUSIONS: A small number of published meta-analyses on environmental factors and risk of ALS was identified, a phenomenon that could be attributed to the challenges in studying a rare neurological disease. More observational studies with adequate sample size and study design are needed to clarify the environmental component of ALS pathogenesis.
Non-genetic risk factors for cutaneous melanoma and keratinocyte skin cancers: An umbrella review of meta-analyses.
BACKGROUND: Skin cancers have a complex disease mechanism, involving both genetic and non-genetic risk factors. Numerous meta-analyses have been published claiming statistically significant associations between non-genetic risk factors and skin cancers without applying a thorough methodological assessment. OBJECTIVE: The present study maps the literature on the non-genetic risk factors of skin cancers, assesses the presence of statistical biases and identifies the associations with robust evidence. METHODS: We searched PubMed up to January 20, 2016 to identify systematic reviews and meta-analyses of observational studies that examined associations between non-genetic factors and skin cancers. For each meta-analysis, we estimated the summary effect size by random-effects and fixed-effects models, the 95% confidence interval and the 95% prediction interval. We also assessed the between-study heterogeneity (I2 metric), evidence for small-study effects and excess significance bias. RESULTS: Forty-four eligible papers were identified and included a total of 85 associations. Twenty-one associations were significant at P<10-6. Fifty-two associations had large or very large heterogeneity. Evidence for small-study effects and excess significance bias was found in fifteen and thirteen associations, respectively. Overall, thirteen associations (actinic keratosis, serum vitamin D, sunburns, and hair color for basal cell carcinoma and density of freckles, eye color, hair color, history of melanoma, skin type, sunburns, premalignant skin lesions, common and atypical nevi for melanoma) presented high level of credibility. CONCLUSION: The majority of meta-analyses on non-genetic risk factors for skin cancers suffered from large between-study heterogeneity and small-study effects or excess significance bias. The associations with convincing and highly suggestive evidence were mainly focused on skin photosensitivity and phenotypic characteristics.
Radiotherapy for prevention of heterotopic ossification of the elbow: a systematic review of the literature.
BACKGROUND: Heterotopic ossification is a pathological process characterized by abnormal formation of bone in nonskeletal tissue. Radiotherapy for heterotopic ossification of the elbow is questionable because of possible adverse effects. METHODS: A systematic review of the literature was conducted in MEDLINE, Scopus, ISI Web of Science, National Institute for Health and Clinical Excellence, National Guideline Clearinghouse, System for Information on Grey Literature in Europe, ClinicalTrials.gov, Cochrane Central Register of Clinical Trials, and Cochrane Database of Systematic Reviews up to April 2012. All published articles assessing interventions including radiotherapy for prevention of heterotopic ossification in the elbow of adult patients were considered. Information was recorded by the first two authors, and disagreements in interpretation were resolved by consensus. RESULTS: In total, 27 studies using radiotherapy for elbow heterotopic ossification were identified (1 randomized clinical trial, 1 case-control study, and 25 case reports and case series) in the literature. Most of them used a single dose of 7.0 Gy. The randomized clinical trial was stopped early because of severe adverse effects (pseudarthrosis) caused by radiation. The case-control study showed that radiotherapy did not effectively prevent recurrence of heterotopic ossification. The case reports and case series mentioned only sparse adverse events. CONCLUSION: The use of radiation therapy for prevention of heterotopic ossification of the elbow is supported by weak evidence.
Tobacco Smoking and Risk for Pulmonary Fibrosis: A Prospective Cohort Study From the UK Biobank.
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an interstitial lung disease of unknown origin. A limited number of small studies show an effect of tobacco smoking on risk of IPF, but second-hand smoking has not been examined. RESEARCH QUESTION: Are smoking-related exposures associated with risk of IPF and does interaction between them exist? STUDY DESIGN AND METHODS: We designed a prospective cohort study using UK Biobank data, including 437,453 nonrelated men and women of White ethnic background (40-69 years of age at baseline). We assessed the effect of tobacco smoking-related exposures on risk for IPF using Cox regression adjusted for age, sex, Townsend deprivation index, and home area population density. We also examined potential additive and multiplicative interaction between these exposures. Multiple imputation with chained equations was used to address missing data. RESULTS: We identified 802 incident IPF cases. We showed an association between smoking status (hazard ratio [HR], 2.12; 95% CI, 1.81-2.47), and maternal smoking (HR, 1.38; 95% CI, 1.18-1.62) with risk of IPF. In ever smokers, a dose-response relationship was observed between pack-years of smoking and risk of IPF (HR per 1-pack-year increase, 1.013; 95% CI, 1.009-1.016). Furthermore, an additive and multiplicative interaction was observed between maternal smoking and smoking status, with a relative excess risk due to interaction of 1.00 (95% CI, 0.45-1.54) and a ratio of HRs of 1.50 (95% CI, 1.05-2.14). INTERPRETATION: Active and maternal tobacco smoking have an independent detrimental effect on risk of IPF and work synergistically. Also, intensity of smoking presents a dose-response association with IPF, strengthening the hypothesis for a potentially causal association.
Elucidating the environmental risk factors for rheumatic diseases: An umbrella review of meta-analyses.
AIMS: Although rheumatic diseases constitute a leading cause of disability, the environmental risk factors for these diseases are not clarified. In the present study, we aim to systematically appraise the epidemiological credibility of the environmental risk factors for rheumatic diseases. METHODS: We systematically searched PubMed to capture meta-analyses of observational studies on environmental risk factors for the most prevalent rheumatic diseases. For each association, we estimated the summary effect size estimate, the 95% confidence and prediction intervals, and the I2 metric. We further examined the presence of small-study effects and excess significance bias. RESULTS: Overall, we identified 30 eligible papers describing 42 associations. Thirty-three associations were statistically significant at P
Environmental factors and risk of multiple sclerosis: Findings from meta-analyses and Mendelian randomization studies.
Multiple sclerosis (MS) is a chronic demyelinating disease that is associated with permanent disability and low quality of life. Development of MS is attributed to a combination of genetic and environmental factors. Genome-wide association studies revealed more than 200 variants that are associated with risk of MS. An umbrella review showed that smoking, history of infectious mononucleosis, and anti-Epstein-Barr virus nuclear antigen (anti-EBNA) immunoglobulin G (IgG) seropositivity are credible risk factors of MS. In the present narrative review, we updated our published umbrella review, showing that body mass index in childhood and adolescence and anti-viral capsid antigen (anti-VCA) IgG seropositivity are additional credible risk factors of MS. In addition, we discuss the findings from Mendelian randomization studies, which present evidence for a potential causal role of serum vitamin D and adulthood body mass index on risk of MS. Finally, we discuss the potential limitations of meta-analyses, umbrella reviews, and Mendelian randomization studies in the search for risk factors of MS.