Showing papers by "Barbara Casadei published in 2021"
TL;DR: The COVID-19 pandemic has led to a sustained reduction in the number of people referred, diagnosed, and treated for colorectal cancer in England, suggesting that, from April to October, 2020, over 3500 fewer people had been diagnosed and treated in England than would have been expected.
210 citations
01 Jun 2021
TL;DR: In this paper, the authors assess how well equipped the UK is to leverage health information technology and apply the principles of a national learning health and care system in response to a major public health shock.
Abstract: Health information technology can support the development of national learning health and care systems, which can be defined as health and care systems that continuously use data-enabled infrastructure to support policy and planning, public health, and personalisation of care. The COVID-19 pandemic has offered an opportunity to assess how well equipped the UK is to leverage health information technology and apply the principles of a national learning health and care system in response to a major public health shock. With the experience acquired during the pandemic, each country within the UK should now re-evaluate their digital health and care strategies. After leaving the EU, UK countries now need to decide to what extent they wish to engage with European efforts to promote interoperability between electronic health records. Major priorities for strengthening health information technology in the UK include achieving the optimal balance between top-down and bottom-up implementation, improving usability and interoperability, developing capacity for handling, processing, and analysing data, addressing privacy and security concerns, and encouraging digital inclusivity. Current and future opportunities include integrating electronic health records across health and care providers, investing in health data science research, generating real-world data, developing artificial intelligence and robotics, and facilitating public-private partnerships. Many ethical challenges and unintended consequences of implementation of health information technology exist. To address these, there is a need to develop regulatory frameworks for the development, management, and procurement of artificial intelligence and health information technology systems, create public-private partnerships, and ethically and safely apply artificial intelligence in the National Health Service.
72 citations
TL;DR: In this article, the authors pointed out that despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield.
46 citations
TL;DR: Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts as mentioned in this paper.
Abstract: Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may ...
43 citations
Boston University1, Kaiser Permanente2, National Institutes of Health3, Harvard University4, University of Oxford5, University of Minnesota6, Maastricht University7, University of Sydney8, Population Health Research Institute9, Cornell University10, University of Texas Southwestern Medical Center11, Duke University12, University of Massachusetts Medical School13, Mayo Clinic14, University of Groningen15, Stanford University16, University Medical Center Groningen17
TL;DR: In this paper, the National Heart, Lung, and Blood Institute's virtual workshop focused on identifying key research priorities related to atrial fibrillation (AF) screening is summarized.
Abstract: Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute's virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.
41 citations
McMaster University1, Population Health Research Institute2, Icahn School of Medicine at Mount Sinai3, Georgia Regents University4, University of Oxford5, University of Lorraine6, University of Alberta7, Mount Sinai Hospital8, Durham University9, University of Arizona10, Cardiovascular Institute of the South11, Rush University12, Pfizer13, Wayne State University14, National University of Singapore15, New York University16, University of Paris17, Baylor College of Medicine18
TL;DR: This paper presented strategies adopted by some organizations to end gender inequality in research leadership, with the goal of harnessing the strength of women and under-represented groups as research leaders and facilitating a just culture in the cardiovascular clinical trial enterprise.
35 citations
London School of Economics and Political Science1, University of Exeter2, University of Cambridge3, John Radcliffe Hospital4, University of Birmingham5, University of Southern Denmark6, Imperial College Healthcare7, Glasgow Caledonian University8, University of York9, Cardiff University10, Belfast Health and Social Care Trust11, University of New South Wales12, University of Southampton13, Imperial College London14, University of London15, Public Health England16, Queen's University Belfast17, University College London18, University of Edinburgh19
TL;DR: The UK has recorded one of the highest death rates associated with COVID-19 globally, whether measured as deaths that are directly attributable to the pandemic or by excess mortality as mentioned in this paper.
35 citations
TL;DR: Canagliflozin has been shown to suppress myocardial NADPH oxidase activity and improve NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects as mentioned in this paper.
Abstract: Aims Recent clinical trials indicate that sodium-glucose cotransporter 2 (SGLT2) inhibitors improve cardiovascular outcomes in heart failure patients, but the underlying mechanisms remain unknown. We explored the direct effects of canagliflozin, an SGLT2 inhibitor with mild SGLT1 inhibitory effects, on myocardial redox signalling in humans. Methods and results Study 1 included 364 patients undergoing cardiac surgery. Right atrial appendage biopsies were harvested to quantify superoxide (O2.-) sources and the expression of inflammation, fibrosis, and myocardial stretch genes. In Study 2, atrial tissue from 51 patients was used ex vivo to study the direct effects of canagliflozin on NADPH oxidase activity and nitric oxide synthase (NOS) uncoupling. Differentiated H9C2 and primary human cardiomyocytes (hCM) were used to further characterize the underlying mechanisms (Study 3). SGLT1 was abundantly expressed in human atrial tissue and hCM, contrary to SGLT2. Myocardial SGLT1 expression was positively associated with O2.- production and pro-fibrotic, pro-inflammatory, and wall stretch gene expression. Canagliflozin reduced NADPH oxidase activity via AMP kinase (AMPK)/Rac1signalling and improved NOS coupling via increased tetrahydrobiopterin bioavailability ex vivo and in vitro. These were attenuated by knocking down SGLT1 in hCM. Canagliflozin had striking ex vivo transcriptomic effects on myocardial redox signalling, suppressing apoptotic and inflammatory pathways in hCM. Conclusions We demonstrate for the first time that canagliflozin suppresses myocardial NADPH oxidase activity and improves NOS coupling via SGLT1/AMPK/Rac1 signalling, leading to global anti-inflammatory and anti-apoptotic effects in the human myocardium. These findings reveal a novel mechanism contributing to the beneficial cardiac effects of canagliflozin.
33 citations
TL;DR: Redox-dependent regulation of lysosomal two-pore channels by PKARIα was sufficient to prevent global calcium release from the sarcoplasmic reticulum in LV myocytes, without affecting intrinsic ryanodine receptor leak or phosphorylation.
Abstract: Background: Kinase oxidation is a critical signaling mechanism through which changes in the intracellular redox state alter cardiac function. In the myocardium, PKARIα (type-1 protein kinase A) can...
29 citations
Royal North Shore Hospital1, National Heart Foundation of Australia2, University of Oxford3, British Heart Foundation4, The Catholic University of America5, La Trobe University6, University of Massachusetts Medical School7, University of Glasgow8, Vanderbilt University9, University of Texas Southwestern Medical Center10, Harvard University11, CSL Limited12, National University of Singapore13, Brigham and Women's Hospital14, Bayer15, Sapporo Medical University16, Monash University, Parkville campus17, University of Manchester18, Cardiovascular Institute of the South19, Shanghai University20, University of Lorraine21
TL;DR: In this paper, the authors focus on the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia.
Abstract: Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic 'buckets'. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased 'omic' approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
24 citations
TL;DR: The EuroHeart data standards as mentioned in this paper are consensual specifications for the representation of data arising from different sources and have the potential to enable reliable between and within country analysis of care and outcomes.
Abstract: Aims Data standards are consensual specifications for the representation of data arising from different sources. If provided with internationally harmonised variables, permissible values, and clinical definitions they have the potential to enable reliable between and within country analysis of care and outcomes. The European Unified Registries for Heart Care Evaluation and Randomised Trials (EuroHeart) is a European Society of Cardiology (ESC) project that allows participating countries to collect patient data to undertake quality improvement, observational studies, drug and device surveillance, and registry-based randomised controlled trials for cardiovascular conditions. This document describes the methodology for development of harmonised data standards for EuroHeart. Methods and results We adopted a five-step process for the development of harmonised data standards. The process includes: (1) identification of clinical domains for data standard development by evaluating specific cardiovascular conditions with high prevalence and opportunities for quality improvement; (2) construction of data standard specifications by systematic review of the literature; (3) selection of variables by a domain specific Working Group using a modified Delphi method; (4) validation of data standards by a domain specific Reference Group; and (5) implementation of the developed data standards into an IT platform. Conclusion This document describes the approach adopted by EuroHeart for the development of clinical data standards for cardiovascular disease. The methodology has been developed and is used by EuroHeart to create a suite of international data standards for cardiovascular diseases. The EuroHeart data standards may be used to systematically capture individual patient data about clinical care and for research.
TL;DR: In this article, the authors investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favorable substrate for atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans.
Abstract: Aims Gp91-containing NADPH oxidases (NOX2) are a significant source of myocardial superoxide production An increase in NOX2 activity accompanies atrial fibrillation (AF) induction and electrical remodelling in animal models and predicts incident AF in humans; however, a direct causal role for NOX2 in AF has not been demonstrated Accordingly, we investigated whether myocardial NOX2 overexpression in mice (NOX2-Tg) is sufficient to generate a favourable substrate for AF and further assessed the effects of atorvastatin, an inhibitor of NOX2, on atrial superoxide production and AF susceptibility Methods and results NOX2-Tg mice showed a 2-25-fold higher atrial protein content of NOX2 compared with wild-type (WT) controls, which was associated with a significant (2-fold) increase in NADPH-stimulated superoxide production (2-hydroxyethidium by HPLC) in left and right atrial tissue homogenates (P = 0004 and P = 0019, respectively) AF susceptibility assessed in vivo by transoesophageal atrial burst stimulation was modestly increased in NOX2-Tg compared with WT (probability of AF induction: 88% vs 69%, respectively; P = 0037), in the absence of significant alterations in AF duration, surface ECG parameters, and LV mass or function Mechanistic studies did not support a role for NOX2 in promoting electrical or structural remodelling, as high-resolution optical mapping of atrial tissues showed no differences in action potential duration and conduction velocity between genotypes In addition, we did not observe any genotype difference in markers of fibrosis and inflammation, including atrial collagen content and Col1a1, Il-1β, Il-6, and Mcp-1 mRNA Similarly, NOX2 overexpression did not have consistent effects on RyR2 Ca2+ leak nor did it affect PKA or CaMKII-mediated RyR2 phosphorylation Finally, treatment with atorvastatin significantly inhibited atrial superoxide production in NOX2-Tg but had no effect on AF induction in either genotype Conclusions Together, these data indicate that whilst atrial NOX2 overexpression may contribute to atrial arrhythmogenesis, NOX2-derived superoxide production does not affect the electrical and structural properties of the atrial myocardium Translational perspective Atrial NOX2-derived superoxide is an independent predictor of postoperative AF in humans and contributes to atrial oxidative stress early after AF induction Whilst experimental models have reported an association of NOX2 with AF-induced remodelling, a causal link between NOX2 activity and AF remains to be established Here we show that overexpression of the human NOX2 gene in mice resulted in a 2-fold higher atrial superoxide production and a modest increase in AF susceptibility, independent of atrial electrical or structural remodelling Short-term treatment with atorvastatin normalized atrial superoxide in NOX2-Tg mice without affecting AF susceptibility Together these findings indicate that atrial NOX2-derived superoxide is more likely a biomarker of AF risk than a primary driver of AF development, and that NOX2 inhibition is unlikely to prevent the new-onset of AF
University of Sydney1, National Heart Foundation of Australia2, University of Oxford3, British Heart Foundation4, The Catholic University of America5, La Trobe University6, University of Massachusetts Medical School7, University of Glasgow8, Jagiellonian University9, Vanderbilt University10, University of Texas Southwestern Medical Center11, Harvard University12, CSL Limited13, National University of Singapore14, Brigham and Women's Hospital15, Bayer16, Sapporo Medical University17, Monash University, Parkville campus18, University of Manchester19, Cardiovascular Institute of the South20, Shanghai University21, University of Lorraine22
TL;DR: In this paper, the authors focus on the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia.
Abstract: While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.
TL;DR: In this article, the authors pointed out that despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield.
Abstract: Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example. Established evidence from other respiratory viruses and emerging evidence for COVID-19 specifically indicates that air pollution alters respiratory defense mechanisms leading to worsened infection severity. Air pollution also contributes to co-morbidities that are known to worsen outcomes amongst those infected with COVID-19, and air pollution may also enhance infection transmission due to its impact on more frequent coughing. Yet despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield. Thus, the urgency to combat air pollution is not diminished, but instead heightened in the context of the pandemic.
TL;DR: In this article, the authors systematically investigated technical and temporal variation of left atrial (LA) 4D flow in atrial fibrillation (AF) and sinus rhythm (SR).
Abstract: Four-dimensional (4D) flow cardiovascular magnetic resonance (CMR) allows sophisticated quantification of left atrial (LA) blood flow, and could yield novel biomarkers of propensity for intra-cardiac thrombus formation and embolic stroke. As reproducibility is critically important to diagnostic performance, we systematically investigated technical and temporal variation of LA 4D flow in atrial fibrillation (AF) and sinus rhythm (SR). Eighty-six subjects (SR, n = 64; AF, n = 22) with wide-ranging stroke risk (CHA2DS2VASc 0–6) underwent LA 4D flow assessment of peak and mean velocity, vorticity, vortex volume, and stasis. Eighty-five (99%) underwent a second acquisition within the same session, and 74 (86%) also returned at 30 (27–35) days for an interval scan. We assessed variability attributable to manual contouring (intra- and inter-observer), and subject repositioning and reacquisition of data, both within the same session (same-day scan–rescan), and over time (interval scan). Within-subject coefficients of variation (CV) and bootstrapped 95% CIs were calculated and compared. Same-day scan–rescan CVs were 6% for peak velocity, 5% for mean velocity, 7% for vorticity, 9% for vortex volume, and 10% for stasis, and were similar between SR and AF subjects (all p > 0.05). Interval-scan variability was similar to same-day scan–rescan variability for peak velocity, vorticity, and vortex volume (all p > 0.05), and higher for stasis and mean velocity (interval scan CVs of 14% and 8%, respectively, both p 0.05). SR subjects showed significantly greater interval-scan variability than AF patients for mean velocity, vortex volume, and stasis (all p 0.05). LA peak velocity and vorticity are the most reproducible and temporally stable novel LA 4D flow biomarkers, and are robust to changes in heart rate, blood pressure, and differences in heart rhythm.
TL;DR: In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment as mentioned in this paper, and there are no effective treatments.
Abstract: Rationale: In diabetic patients, heart failure with predominant left ventricular (LV) diastolic dysfunction is a common complication for which there is no effective treatment. Oxidation of the NOS ...
TL;DR: In this paper, left atrial (LA) size and function are known predictors of new onset atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) patients.
Abstract: Background Left atrial (LA) size and function are known predictors of new onset atrial fibrillation (AF) in hypertrophic cardiomyopathy (HCM) patients. Components of LA deformation including reservoir, conduit, and booster function provide additional information on atrial mechanics. Whether or not LA deformation can augment our ability to predict the risk of new onset AF in HCM patients beyond standard measurements is unknown. Methods We assessed LA size, function, and deformation on cardiovascular magnetic resonance (CMR) in 238 genotyped HCM patients and compared this with twenty age, sex, blood pressure and body mass index matched control subjects. We further evaluated the determinants of new onset AF in HCM patients. Results Compared to control subjects, HCM patients had higher LA antero-posterior diameter, lower LA ejection fraction and lower LA reservoir (19.9 [17.1, 22.2], 21.6 [19.9, 22.9], P = 0.047) and conduit strain (10.6 ± 4.4, 13.7 ± 3.3, P = 0.002). LA booster strain did not differ between healthy controls and HCM patients, but HCM patients who developed new onset AF (n = 33) had lower booster strain (7.6 ± 3.3, 9.5 ± 3.0, P = 0.001) than those that did not (n = 205). In separate multivariate models, age, LA ejection fraction, and LA booster and reservoir strain were each independent determinants of AF. Age ≥ 55 years was the strongest determinant (HR 6.62, 95% CI 2.79-15.70), followed by LA booster strain ≤ 8% (HR 3.69, 95% CI 1.81-7.52) and LA reservoir strain ≤ 18% (HR 2.56, 95% CI 1.24-5.27). Conventional markers of HCM phenotypic severity, age and sudden death risk factors were associated with LA strain components. Conclusions LA strain components are impaired in HCM and, together with age, independently predicted the risk of new onset AF. Increasing age and phenotypic severity were associated with LA strain abnormalities. Our findings suggest that the routine assessment of LA strain components and consideration of age could augment LA size in predicting risk of AF, and potentially guide prophylactic anticoagulation use in HCM.
TL;DR: In this paper, the authors investigated whether exposure to stroke risk factors is sufficient to alter left atrial (LA) blood flow even in the presence of sinus rhythm (SR), and found that patients at moderate-to-high stroke risk display altered LA flow characteristics in SR in association with an LA myopathic phenotype and LV diastolic dysfunction, regardless of a history of AF.
Abstract: AIMS Altered left atrial (LA) blood flow characteristics account for an increase in cardioembolic stroke risk in atrial fibrillation (AF). Here, we aimed to assess whether exposure to stroke risk factors is sufficient to alter LA blood flow even in the presence of sinus rhythm (SR). METHODS AND RESULTS We investigated 95 individuals: 37 patients with persistent AF, who were studied before and after cardioversion [Group 1; median CHA2DS2-VASc = 2.0 (1.5-3.5)]; 35 individuals with no history of AF but similar stroke risk to Group 1 [Group 2; median CHA2DS2-VASc = 3.0 (2.0-4.0)]; and 23 low-risk individuals in SR [Group 3; median CHA2DS2-VASc = 0.0 (0.0-0.0)]. Cardiac function and LA flow characteristics were evaluated using cardiac magnetic resonance. Before cardioversion, Group 1 displayed impaired left ventricular (LV) and LA function, reduced LA flow velocities and vorticity, and a higher normalized vortex volume (all P < 0.001 vs. Groups 2 and 3). After restoration of SR at ≥4-week post-cardioversion, LV systolic function and LA flow parameters improved significantly (all P < 0.001 vs. pre-cardioversion) and were no longer different from those in Group 2. However, in the presence of SR, LA flow peak and mean velocity, and vorticity were lower in Groups 1 and 2 vs. Group 3 (all P < 0.01), and were associated with impaired LA emptying fraction (LAEF) and LV diastolic dysfunction. CONCLUSION Patients at moderate-to-high stroke risk display altered LA flow characteristics in SR in association with an LA myopathic phenotype and LV diastolic dysfunction, regardless of a history of AF.
TL;DR: In this paper, the authors pointed out that despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield.
Abstract: Although the attention of the world and the global health community specifically is deservedly focused on the COVID-19 pandemic, other determinants of health continue to have large impacts and may also interact with COVID-19. Air pollution is one crucial example. Established evidence from other respiratory viruses and emerging evidence for COVID-19 specifically indicates that air pollution alters respiratory defense mechanisms leading to worsened infection severity. Air pollution also contributes to co-morbidities that are known to worsen outcomes amongst those infected with COVID-19, and air pollution may also enhance infection transmission due to its impact on more frequent coughing. Yet despite the massive disruption of the COVID-19 pandemic, there are reasons for optimism: broad societal lockdowns have shown us a glimpse of what a future with strong air pollution measures could yield. Thus, the urgency to combat air pollution is not diminished, but instead heightened in the context of the pandemic.
University of Virginia Health System1, MedStar Health2, Brigham and Women's Hospital3, National Institutes of Health4, Tufts Medical Center5, McGill University6, Charité7, University of Oxford8, Yale University9, University of Calgary10, King's College London11, University of Michigan12, Northwestern University13, Erasmus University Rotterdam14, University of Birmingham15, University of Aberdeen16, Cornell University17, University of Glasgow18, Houston Methodist Hospital19, University of Bristol20, University of Pennsylvania21
TL;DR: In this paper, the authors identify predictors of major clinically important atrial fibrillation endpoints in hypertrophic cardiomyopathy, defined as requiring electrical cardioversion, catheter ablation, hospitalization for >24 h, or clinical decisions to accept permanent AF.
TL;DR: In this paper, the authors used Cox proportional hazards models to estimate the covariate adjusted hazard ratios (HRs) describing the association of Atrial fibrillation with weight, measures of adiposity [fat mass (FM), waist circumference (WC), and LM, and their independent relevance, by sex.
Abstract: Background Atrial fibrillation (AF) has a higher prevalence in men than in women and is associated with measures of adiposity and lean mass (LM). However, it remains uncertain whether the risks of AF associated with these measures vary by sex. Methods Among 477 904 UK Biobank participants aged 40-69 without prior AF, 23 134 incident AF cases were identified (14 400 men, 8734 women; median follow-up 11.1 years). Cox proportional hazards models were used to estimate the covariate adjusted hazard ratios (HRs) describing the association of AF with weight, measures of adiposity [fat mass (FM), waist circumference (WC)] and LM, and their independent relevance, by sex. Results Weight and WC were independently associated with risk of AF [HR: 1.25 (1.23-1.27) per 10 kg, HR: 1.11 (1.09-1.14) per 10 cm, respectively], with comparable effects in both sexes. The association with weight was principally driven by LM, which, per 5 kg, conferred double the risk of AF compared with FM when mutually adjusted [HR: 1.20 (1.19-1.21), HR: 1.10 (1.09-1.11), respectively]; however, the effect of LM was weaker in men than in women (p-interaction = 4.3 x 10-9). Comparing the relative effects of LM, FM and WC identified different patterns within each sex; LM was the strongest predictor for both, whereas WC was stronger than FM in men but not in women. Conclusions LM and FM (as constituents of weight) and WC are risk factors for AF. However, the independent relevance of general adiposity for AF was more limited in men than in women. The relevance of both WC and LM suggests a potentially important role for visceral adiposity and muscle mass in AF development.
TL;DR: In this article, the potential causal relevance of ECG parameters on risk of atrial fibrillation using mendelian randomisation (MR) was examined, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases).
Abstract: Background Atrial electrical and structural remodelling in older individuals with cardiovascular risk factors has been associated with changes in surface electrocardiographic (ECG) parameters (e.g., prolongation of the PR interval) and higher risks of atrial fibrillation (AF). However, it has been difficult to establish whether altered ECG parameters are the cause or a consequence of the myocardial substrate leading to AF. This study aimed to examine the potential causal relevance of ECG parameters on risk of AF using mendelian randomisation (MR). Methods and findings Weighted genetic scores explaining lifelong differences in P-wave duration, PR interval, and QT interval were constructed, and associations between these ECG scores and risk of AF were estimated among 278,792 UK Biobank participants (mean age: 57 years at recruitment; 19,132 AF cases). The independent genetic variants contributing to each of the separate ECG scores, and their corresponding weights, were based on published genome-wide association studies. In UK Biobank, genetic scores representing a 5 ms longer P-wave duration or PR interval were significantly associated with lower risks of AF (odds ratio [OR] 0.91; 95% confidence interval [CI]: 0.87-0.96, P = 2 × 10-4 and OR 0.94; 95% CI: 0.93-0.96, P = 2 × 10-19, respectively), while longer QT interval was not significantly associated with AF. These effects were independently replicated among a further 17,931 AF cases from the AFGen Consortium. Investigation of potential mechanistic pathways showed that differences in ECG parameters associated with specific ion channel genes had effects on risk of AF consistent with the overall scores, while the overall scores were not associated with changes in left atrial size. Limitations of the study included the inherent assumptions of MR, restriction to individuals of European ancestry, and possible restriction of results to the normal ECG ranges represented in UK Biobank. Conclusions In UK Biobank, we observed evidence suggesting a causal relationship between lifelong differences in ECG parameters (particularly PR interval) that reflect longer atrial conduction times and a lower risk of AF. These findings, which appear to be independent of atrial size and concomitant cardiovascular comorbidity, support the relevance of varying mechanisms underpinning AF and indicate that more individualised treatment strategies warrant consideration.
Université Paris-Saclay1, Maastricht University2, University of Duisburg-Essen3, University of Glasgow4, Maastricht University Medical Centre5, University of Florence6, Manchester Academic Health Science Centre7, John Radcliffe Hospital8, University of Milan9, University of Montpellier10, University of Oxford11, Katholieke Universiteit Leuven12
TL;DR: The combination of three simple characteristics (age, sex, BMI) and three biomarkers (BMP10, ANG2, and FGF23) robustly identifies patients with AF and enables targeted screening for AF and provides a platform to develop personalised prevention and treatment in patients withAF.
Abstract: Background: Early detection of atrial fibrillation (AF) and subsequent initiation of anticoagulation and rhythm control therapy markedly reduce stroke, cardiovascular death, and heart failure, but unselected ECG screening for AF is time- and resource-intensive. Combining biomarkers reflecting different biological processes may identify patients at high risk of AF, enabling targeted ECG screening.
Methods: We systematically reviewed literature and patent information to define candidate biomarkers for AF detection. The top 12 biomarkers identified through this process were quantified on a high-precision, high-throughput platform in 1485 consecutive patients at risk for AF presenting acutely to hospital (median age 69 years [Q1, Q3 60,78]; 60% male). Patients had either known AF (45%) or AF ruled out by 7-day ECG-monitoring. A model simultaneously considering 7 key clinical characteristics and all biomarkers was developed in a randomly sampled discovery cohort (n=933) and validated in the remaining patients (n=552). Neural networks were also applied.
Findings: Using backward elimination, a model using age, sex, body mass index (BMI), BMP10, ANG2, and FGF23 discriminated between patients with and without AF with an AUC of 0·743 [95% confidence interval (CI) 0·712-0·775]. The biomarkers represent distinct pathways relevant for atrial cardiomyopathy and AF, namely hypertrophy and fibrosis (FGF23), endothelial dysfunction (ANG2), and atrial oxidative stress and the genomic predisposition to AF (BMP10). The SHAP procedure for neural networks identified the same variables as the regression. The validation yielded an AUC of 0·719 (95%CI 0·677, 0·762), corroborated using deep neural networks (AUC 0·784 [95%CI 0·745, 0·822]).
Interpretation: The combination of three simple characteristics (age, sex, BMI) and three biomarkers (BMP10, ANG2, and FGF23) robustly identifies patients with AF. Such an approach enables targeted screening for AF and provides a platform to develop personalised prevention and treatment in patients with AF.
Funding Statement: This work was partially supported by the European Commission (grant agreements no. 633196 [CATCH ME]) to PKi, LF, BC, SH, SK, LM, MFS, US, and no. 116074 [BigData@Heart EU IMI] to PKi, British Heart Foundation (FS/13/43/30324 and (AA/18/2/34218) to PKi and LF), German Centre for Cardiovascular Research supported by the German Ministry of Education and Research (DZHK, via a grant to AFNET to PKi), and Leducq Foundation (14CVD01) to PKi.
Declaration of Interests: LF has received institutional research grants and non-financial support from European Union, British Heart Foundation, Medical Research Council (UK), and DFG and Gilead. PKi has received additional support for research from the European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Heart Research, from several drug and device companies active in atrial fibrillation, honoraria from several such companies. PKi and LF are listed as inventors on two patents held by University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). PKa is an employee of Roche Diagnostics GmbH. AZ is an employee of Roche Diagnostics Intl. All other authors have reported no relationships relevant to the contents of this paper to disclose.
Ethics Approval Statement: This study complied with the Declaration of Helsinki, was approved by the National Research Ethics Service Committee (IRAS ID 97753), and was sponsored by the University of Birmingham.