Publications by authors named "John Chambers"

417 Publications

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups.

Lipids Health Dis 2021 Sep 21;20(1):113. Epub 2021 Sep 21.

Duke-NUS Medical School, Singapore, 169857, Singapore.

Background: Hypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk.

Methods: We performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD.

Results: One rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042).

Conclusions: Our results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12944-021-01531-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456544PMC
September 2021

First phase ejection fraction in aortic stenosis: A useful new measure of early left ventricular systolic dysfunction.

J Clin Ultrasound 2021 Sep 10. Epub 2021 Sep 10.

Cardiothoracic Centre, Guy's and St. Thomas' Hospitals, London, UK.

In aortic stenosis (AS), a left ventricular (LV) ejection fraction (EF) <50% or symptoms are class I indications for aortic valve intervention. However, an EF <50% may be too conservative since subendocardial fibrosis may already have developed. An earlier marker of LV systolic dysfunction is therefore needed and first phase EF (EF1) is a promising new candidate. It is the EF measured over early systole to the point of maximum transaortic blood flow. It may be low in the presence of preserved total LV EF since the heart may compensate by recruiting myosin motors in later systole. The EF1 is inversely related to the grade of AS and directly related to markers of subendocardial fibrosis like late gadolinium enhancement on cardiac magnetic resonance scanning. A reduced EF1 (<25%) predicts adverse clinical events better that total EF and global longitudinal strain. We suggest that it is worth exploring as an indication for surgery in patients with asymptomatic severe AS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcu.23063DOI Listing
September 2021

Dobutamine stress echocardiography for low gradient aortic stenosis: current practice in Poland.

Kardiol Pol 2021 ;79(5):491-492

Cardiothoracic Centre, Guy's and Saint Thomas' Hospital, London, United Kingdom.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.33963/KP.2021.0014DOI Listing
June 2021

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Nat Commun 2021 06 9;12(1):3505. Epub 2021 Jun 9.

Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23556-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8190084PMC
June 2021

First-phase ejection fraction by cardiovascular magnetic resonance predicts outcomes in aortic stenosis.

J Cardiovasc Magn Reson 2021 06 10;23(1):73. Epub 2021 Jun 10.

British Heart Foundation Centre of Research Excellence, King's College London, London, UK.

Background: First-phase ejection fraction (EF1; the ejection fraction measured during active systole up to the time of maximal aortic flow) measured by transthoracic echocardiography (TTE) is a powerful predictor of outcomes in patients with aortic stenosis. We aimed to assess whether cardiovascular magnetic resonance (CMR) might provide more precise measurements of EF1 than TTE and to examine the correlation of CMR EF1 with measures of fibrosis.

Methods: In 141 patients with at least mild aortic stenosis, we measured CMR EF1 from a short-axis 3D stack and compared its variability with TTE EF1, and its associations with myocardial fibrosis and clinical outcome (aortic valve replacement (AVR) or death).

Results: Intra- and inter-observer variation of CMR EF1 (standard deviations of differences within and between observers of 2.3% and 2.5% units respectively) was approximately 50% that of TTE EF1. CMR EF1 was strongly predictive of AVR or death. On multivariable Cox proportional hazards analysis, the hazard ratio for CMR EF1 was 0.93 (95% confidence interval 0.89-0.97, p = 0.001) per % change in EF1 and, apart from aortic valve gradient, CMR EF1 was the only imaging or biochemical measure independently predictive of outcome. Indexed extracellular volume was associated with AVR or death, but not after adjusting for EF1.

Conclusions: EF1 is a simple robust marker of early left ventricular impairment that can be precisely measured by CMR and predicts outcome in aortic stenosis. Its measurement by CMR is more reproducible than that by TTE and may facilitate left ventricular structure-function analysis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12968-021-00756-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8191208PMC
June 2021

The trans-ancestral genomic architecture of glycemic traits.

Nat Genet 2021 06 31;53(6):840-860. Epub 2021 May 31.

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands.

Glycemic traits are used to diagnose and monitor type 2 diabetes and cardiometabolic health. To date, most genetic studies of glycemic traits have focused on individuals of European ancestry. Here we aggregated genome-wide association studies comprising up to 281,416 individuals without diabetes (30% non-European ancestry) for whom fasting glucose, 2-h glucose after an oral glucose challenge, glycated hemoglobin and fasting insulin data were available. Trans-ancestry and single-ancestry meta-analyses identified 242 loci (99 novel; P < 5 × 10), 80% of which had no significant evidence of between-ancestry heterogeneity. Analyses restricted to individuals of European ancestry with equivalent sample size would have led to 24 fewer new loci. Compared with single-ancestry analyses, equivalent-sized trans-ancestry fine-mapping reduced the number of estimated variants in 99% credible sets by a median of 37.5%. Genomic-feature, gene-expression and gene-set analyses revealed distinct biological signatures for each trait, highlighting different underlying biological pathways. Our results increase our understanding of diabetes pathophysiology by using trans-ancestry studies for improved power and resolution.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-021-00852-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610958PMC
June 2021

Specialists give better care than generalists for mitral valve disease.

Authors:
John B Chambers

Eur J Cardiothorac Surg 2021 07;60(2):274-275

Cardiothoracic Centre, Guy's and St Thomas' Hospitals, London, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ejcts/ezab103DOI Listing
July 2021

Automated Left Ventricular Dimension Assessment Using Artificial Intelligence Developed and Validated by a UK-Wide Collaborative.

Circ Cardiovasc Imaging 2021 05 17;14(5):e011951. Epub 2021 May 17.

Imperial College London (J.P.H., C.C.S., G.D.C., K.A., K.V., D.P.F., M.J.S.-S.).

Background: requires training and validation to standards expected of humans. We developed an online platform and established the Unity Collaborative to build a dataset of expertise from 17 hospitals for training, validation, and standardization of such techniques.

Methods: The training dataset consisted of 2056 individual frames drawn at random from 1265 parasternal long-axis video-loops of patients undergoing clinical echocardiography in 2015 to 2016. Nine experts labeled these images using our online platform. From this, we trained a convolutional neural network to identify keypoints. Subsequently, 13 experts labeled a validation dataset of the end-systolic and end-diastolic frame from 100 new video-loops, twice each. The 26-opinion consensus was used as the reference standard. The primary outcome was precision SD, the SD of the differences between AI measurement and expert consensus.

Results: In the validation dataset, the AI's precision SD for left ventricular internal dimension was 3.5 mm. For context, precision SD of individual expert measurements against the expert consensus was 4.4 mm. Intraclass correlation coefficient between AI and expert consensus was 0.926 (95% CI, 0.904-0.944), compared with 0.817 (0.778-0.954) between individual experts and expert consensus. For interventricular septum thickness, precision SD was 1.8 mm for AI (intraclass correlation coefficient, 0.809; 0.729-0.967), versus 2.0 mm for individuals (intraclass correlation coefficient, 0.641; 0.568-0.716). For posterior wall thickness, precision SD was 1.4 mm for AI (intraclass correlation coefficient, 0.535 [95% CI, 0.379-0.661]), versus 2.2 mm for individuals (0.366 [0.288-0.462]). We present all images and annotations. This highlights challenging cases, including poor image quality and tapered ventricles.

Conclusions: Experts at multiple institutions successfully cooperated to build a collaborative AI. This performed as well as individual experts. Future echocardiographic AI research should use a consensus of experts as a reference. Our collaborative welcomes new partners who share our commitment to publish all methods, code, annotations, and results openly.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCIMAGING.120.011951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8136463PMC
May 2021

Exercise testing in patients with aortic stenosis: clinically useful.

Pol Arch Intern Med 2021 04 29;131(4):324-325. Epub 2021 Apr 29.

Cardiothoracic Centre, Guy’s and Saint Thomas’ Hospital, London, United Kingdom

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.20452/pamw.15978DOI Listing
April 2021

Low uptake of COVID-19 prevention behaviours and high socioeconomic impact of lockdown measures in South Asia: Evidence from a large-scale multi-country surveillance programme.

SSM Popul Health 2021 Mar 13;13:100751. Epub 2021 Feb 13.

Madras Diabetes Research Foundation, Chennai, India.

Background: South Asia has become a major epicentre of the COVID-19 pandemic. Understanding South Asians' awareness, attitudes and experiences of early measures for the prevention of COVID-19 is key to improving the effectiveness and mitigating the social and economic impacts of pandemic responses at a critical time for the Region.

Methods: We assessed the knowledge, behaviours, health and socio-economic circumstances of 29,809 adult men and women, at 93 locations across four South Asian countries. Data were collected during the national lockdowns implemented from March to July 2020, and compared with data collected prior to the pandemic as part of an ongoing prospective surveillance initiative.

Results: Participants were 61% female, mean age 45.1 years. Almost half had one or more chronic disease, including diabetes (16%), hypertension (23%) or obesity (16%). Knowledge of the primary COVID-19 symptoms and transmission routes was high, but access to hygiene and personal protection resources was low (running water 63%, hand sanitisers 53%, paper tissues 48%). Key preventive measures were not widely adopted. Knowledge, access to, and uptake of COVID-19 prevention measures were low amongst people from disadvantaged socio-economic groups. Fifteen percent of people receiving treatment for chronic diseases reported loss of access to long-term medications; 40% reported symptoms suggestive of anxiety or depression. The prevalence of unemployment rose from 9.3% to 39.4% (P < 0.001), and household income fell by 52% (P < 0.001) during the lockdown. Younger people and those from less affluent socio-economic groups were most severely impacted. Sedentary time increased by 32% and inadequate fruit and vegetable intake increased by 10% (P < 0.001 for both), while tobacco and alcohol consumption dropped by 41% and 80%, respectively (P < 0.001), during the lockdown.

Conclusions: Our results identified important knowledge, access and uptake barriers to the prevention of COVID-19 in South Asia, and demonstrated major adverse impacts of the pandemic on chronic disease treatment, mental health, health-related behaviours, employment and household finances. We found important sociodemographic differences for impact, suggesting a widening of existing inequalities. Our findings underscore the need for immediate large-scale action to close gaps in knowledge and access to essential resources for prevention, along with measures to safeguard economic production and mitigate socio-economic impacts on the young and the poor.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ssmph.2021.100751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902538PMC
March 2021

Predictors of true-severe classical low-flow low-gradient aortic stenosis at resting echocardiography.

Int J Cardiol 2021 07 1;335:93-97. Epub 2021 Mar 1.

Department of Cardiology, Kepler University Hospital, Medical Faculty Johannes Kepler University Linz, Krankenhausstrasse 9, 4020 Linz, Austria; Paracelsus Medical University Salzburg, Salzburg, Austria.

Background: Classical low-flow, low-gradient (LF/LG) aortic stenosis (AS) is subclassified into a true-severe (TS) and a pseudo-severe (PS) subform using low-dose dobutamine stress echocardiography (DSE). In clinical practice a resting peak jet velocity (Vmax) >3.5 m/s or a mean transvalvular gradient (MPG) >35 mmHg suggests the presence of TS classical LF/LG AS, but there is no data to support this. The aim of this study was therefore to investigate whether a resting Vmax >3.5 m/s or MPG >35 mmHg reliably predicted diagnosis of TS classical LF/LG AS.

Methods: One hundred (100) consecutive patients with classical LF/LG AS were prospectively recruited. All patients underwent DSE for subcategorization. The impact of Vmax and MPG for the presence of the TS subform were analyzed.

Results: TS classical LF/LG AS was diagnosed in 72 patients. Resting Vmax and resting MPG predicted true-severity with an ROC-AUC of 0.737 (95%CI: 0.635-0.838; p < 0.001) and 0.725 (95%CI: 0.615-0.834; p < 0.001), respectively. The optimal positive predictive values (PPV) for the diagnosis of TS classical LF/LG AS were obtained with a resting Vmax >3.5 m/s or resting MPG >35 mmHg. In a multivariate logistic regression analysis, Vmax >3.5 m/s was independently associated with a 5.33-fold odds-ratio of TS classical LF/LG AS (OR 5.33; 95%CI: 1.34-21.18, p = 0.018).

Conclusions: TS classical LF/LG AS can be reliably predicted by a resting Vmax >3.5 m/s or a resting MPG >35 mmHg. Further imaging for subclassification is not needed in this situation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2021.02.070DOI Listing
July 2021

Pharmacokinetics, efficacy and convulsive dose of articaine hydrochloride in goat kids.

Vet Anaesth Analg 2021 Mar 29;48(2):264-271. Epub 2020 Dec 29.

School of Veterinary Science, Massey University, Palmerston North, New Zealand.

Objective: To investigate the pharmacokinetics, efficacy and convulsive dose of articaine hydrochloride in goat kids.

Study Design: Experimental prospective study.

Animals: A total of 18 (n = 6 animals per experiment) male Saanen goat kids (2-4 weeks old).

Methods: The study consisted of three experiments. The first determined the pharmacokinetics of articaine following intravenous administration of articaine hydrochloride (8 mg kg). The second experiment investigated the anaesthetic efficacy and pharmacokinetics following cornual nerve block using 1.5% articaine hydrochloride. Anaesthesia of horn buds was evaluated using the response to pinprick test. Non-compartmental analysis was used. The final experiment determined the convulsive dose of articaine and its corresponding plasma concentration following intravenous infusion of articaine hydrochloride (4 mg kg minute). Data are shown as mean ± standard deviation.

Results: The mean terminal half-life (t), mean volume of distribution at steady state (Vd) and mean plasma clearance (CL) of articaine following intravenous administration were 0.66 hour, 3.81 L kg and 5.33 L hour kg, respectively. After cornual nerve block, the mean maximum plasma concentration of articaine was 587 ng mL at 0.22 hour and its mean t was 1.26 hours. Anaesthesia of horn buds was observed within 4 minutes following cornual nerve block. The mean dose required to produce convulsions was 16.24 mg kg and mean convulsive plasma concentrations of articaine and articainic acid were 9905 and 1517 ng mL, respectively.

Conclusions: Intravenous administration of 8 mg kg of articaine hydrochloride did not cause any adverse effects. Pharmacokinetic data suggest that articaine was rapidly eliminated and cleared. Cornual nerve block using 1.5% articaine hydrochloride alleviated the response to the acute nociceptive stimulus during disbudding.

Clinical Relevance: Articaine hydrochloride appears to be a safe and effective local anaesthetic for disbudding in goat kids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.vaa.2019.12.012DOI Listing
March 2021

The electrocardiogram: Still a useful marker for LV fibrosis in aortic stenosis.

J Electrocardiol 2021 Mar-Apr;65:82-87. Epub 2021 Jan 26.

Cardiothoracic Centre, Guy's and Saint Thomas' Hospital, London, UK.

Left ventricular (LV) strain on the electrocardiogram (ECG) (down-sloping, convex ST-segment depression with asymmetric T-wave inversion in leads V5 and V6) reflects fibrosis as a result of subendocardial ischemia. It is associated with a significantly increased risk of cardiovascular events independent of the presence of LV hypertrophy on the echocardiogram or cardiac magnetic resonance (CMR) scan. Ongoing studies of early aortic valve replacement in asymptomatic patients with severe aortic stenosis are using ECG changes as a marker of possible fibrosis shown by midwall late gadolinium enhancement on CMR. However, until these studies report, it is still reasonable to respond to LV strain on the ECG by tightening control of systemic hypertension and consider intervention in cases where indications are otherwise in borderline.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jelectrocard.2021.01.008DOI Listing
July 2021

The clinical significance and prognostic value of right ventricular wall tension in moderate or severe tricuspid regurgitation.

Future Cardiol 2021 Feb 3. Epub 2021 Feb 3.

Cardiothoracic Center, Guy's & St Thomas' NHS Foundation Trust, London, UK.

We aim to explore the determinants of right ventricular wall tension (RV WT [RV base-to-apex length multiplied by systolic pulmonary artery pressure] and association with all-cause mortality in patients with moderate-to-severe tricuspid regurgitation.  Of total, 180 patients (71 ± 15years, 54% females) were included. An increased RV WT was defined as >3300 mmHgxmm. Patients with increased RV WT (n = 85, 47%) were more likely to be male and taller than patients with normal RV WT. In a multivariable-adjusted model, increased RV WT was associated with a 2.6-fold higher risk of all-cause mortality (HR: 2.59, 95% CI: 1.65-4.06). In patients with significant tricuspid regurgitation, an increased RV WT was common, and associated with a 2.6-fold higher risk of all-cause mortality. Male sex was the only independent determinant.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2217/fca-2020-0176DOI Listing
February 2021

Higher Acceleration/Ejection Time Ratio Predicts Impaired Outcome in Aortic Valve Stenosis.

Circ Cardiovasc Imaging 2021 01 19;14(1):e011467. Epub 2021 Jan 19.

Department of Clinical Science, University of Bergen, Norway (E.E., E.G.).

Background: Acceleration time (AT)/ejection time (ET) ratio is a marker of aortic valve stenosis (AS) severity and predicts outcome in moderate-severe AS.

Methods: We explored the association of increased AT/ET ratio on prognosis in 1530 asymptomatic patients with presumably mild-moderate AS, normal ejection fraction, and without known diabetes or cardiovascular disease. Patients were part of the SEAS study (Simvastatin Ezetimibe Aortic Stenosis). Patients were grouped according to the optimal AT/ET ratio threshold to predict cardiovascular death and heart failure hospitalization. Low-gradient severe AS was identified as combined valve area ≤1.0 cm and mean gradient <40 mm Hg. Outcome was assessed in Cox regression analyses, and results are reported as hazard ratio and 95% CI.

Results: Higher AT/ET ratio was significantly associated with lower systolic blood pressure, lower left ventricular ejection fraction, lower stress-corrected midwall shortening, low flow, and with higher left ventricular mass and higher peak aortic jet velocity. AT/ET ratio ≥0.32 provided the optimal cutoff for predicting incident cardiovascular death and heart failure hospitalization in the total study sample. In patients with low-gradient severe AS, this threshold was >0.32. AT/ET ratio ≥0.32 had a 79% higher risk of cardiovascular death and heart failure hospitalization (hazard ratio, 1.79 [95% CI, 1.20-2.68]). In patients with low-gradient severe AS, AT/ET ratio >0.32 was associated with a 2-fold higher risk of cardiovascular death and heart failure hospitalization (hazard ratio, 2.15 [95% CI, 1.22-3.77]).

Conclusions: In asymptomatic nonsevere AS and low-gradient severe AS, higher AT/ET ratio was associated with increased cardiovascular morbidity and mortality. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00092677.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCIMAGING.120.011467DOI Listing
January 2021

DNA methylation and lipid metabolism: an EWAS of 226 metabolic measures.

Clin Epigenetics 2021 01 7;13(1). Epub 2021 Jan 7.

Center for Life Course Health Research, University of Oulu, Oulu University Hospital, Oulu, Finland.

Background: The discovery of robust and trans-ethnically replicated DNA methylation markers of metabolic phenotypes, has hinted at a potential role of epigenetic mechanisms in lipid metabolism. However, DNA methylation and the lipid compositions and lipid concentrations of lipoprotein sizes have been scarcely studied. Here, we present an epigenome-wide association study (EWAS) (N = 5414 total) of mostly lipid-related metabolic measures, including a fine profiling of lipoproteins. As lipoproteins are the main players in the different stages of lipid metabolism, examination of epigenetic markers of detailed lipoprotein features might improve the diagnosis, prognosis, and treatment of metabolic disturbances.

Results: We conducted an EWAS of leukocyte DNA methylation and 226 metabolic measurements determined by nuclear magnetic resonance spectroscopy in the population-based KORA F4 study (N = 1662) and replicated the results in the LOLIPOP, NFBC1966, and YFS cohorts (N = 3752). Follow-up analyses in the discovery cohort included investigations into gene transcripts, metabolic-measure ratios for pathway analysis, and disease endpoints. We identified 161 associations (p value < 4.7 × 10), covering 16 CpG sites at 11 loci and 57 metabolic measures. Identified metabolic measures were primarily medium and small lipoproteins, and fatty acids. For apolipoprotein B-containing lipoproteins, the associations mainly involved triglyceride composition and concentrations of cholesterol esters, triglycerides, free cholesterol, and phospholipids. All associations for HDL lipoproteins involved triglyceride measures only. Associated metabolic measure ratios, proxies of enzymatic activity, highlight amino acid, glucose, and lipid pathways as being potentially epigenetically implicated. Five CpG sites in four genes were associated with differential expression of transcripts in blood or adipose tissue. CpG sites in ABCG1 and PHGDH showed associations with metabolic measures, gene transcription, and metabolic measure ratios and were additionally linked to obesity or previous myocardial infarction, extending previously reported observations.

Conclusion: Our study provides evidence of a link between DNA methylation and the lipid compositions and lipid concentrations of different lipoprotein size subclasses, thus offering in-depth insights into well-known associations of DNA methylation with total serum lipids. The results support detailed profiling of lipid metabolism to improve the molecular understanding of dyslipidemia and related disease mechanisms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13148-020-00957-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789600PMC
January 2021

Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals.

Nat Genet 2020 12 23;52(12):1314-1332. Epub 2020 Nov 23.

Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.

Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to ~1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency ≤ 0.01) variant BP associations (P < 5 × 10), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were ~8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41588-020-00713-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610439PMC
December 2020

Pressure Algometry Validation and Determination of Efficacy of Articaine Hydrochloride Ring Block in Antler Removal in Red Deer ().

Animals (Basel) 2020 Nov 3;10(11). Epub 2020 Nov 3.

Animal Welfare Science and Bioethics Centre, School of Veterinary Science, Massey University, Palmerston North 4474, New Zealand.

New Zealand deer farming centres on the production of meat and velvet antler. Velvet antler removal is a painful procedure and currently, New Zealand Animal Welfare regulations dictate surgical removal of velvet antlers under lignocaine anaesthesia. To improve our knowledge on the efficacy and duration of other local anaesthetics to mitigate pain after antler removal, it is important to accurately assess and quantify pain arising from antler removal. Therefore, the current study was designed to validate mechanical nociceptive threshold (MNT) testing using a Wagner hand-held algometer, and to apply this methodology to assess the efficacy and duration of action of articaine for antler removal in deer. Baseline force (N) required to elicit the nociceptive response was recorded in 40 yearling male red deer on three alternate days. Ten of the 40 animals were selected for antler removal after administration of 4% articaine hydrochloride as a ring block. The duration of analgesic efficacy of articaine was assessed by algometry across 5 time points. There was a significant difference in MNTs among the three days (day 3 versus day 1 ( < 0.0001), day 2 versus day 1 ( < 0.0001), and day 1 versus day 2 ( < 0.01)). Positive correlations were observed between weight, antler length and thresholds. The MNT values remained above 20N for 6 h after removal of velvet antlers under the articaine ring block. This study provides valuable information about the use of MNT in red deer. These findings lay a foundation for future studies in the topics of peri-operative and postoperative pain management in deer antler removal, and a possible alternative use for articaine.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ani10112023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693159PMC
November 2020

Investigating causal relationships between Body Mass Index and risk of atopic dermatitis: a Mendelian randomization analysis.

Sci Rep 2020 09 17;10(1):15279. Epub 2020 Sep 17.

Lee Kong Chian School of Medicine, NTU, Singapore, Singapore.

Population studies suggest that atopic dermatitis (AD) is associated with an increased risk of obesity, however a causal relationship between these two conditions remains to be established. We therefore use Mendelian randomization (MR) to evaluate whether obesity and AD are causally interlinked. We used summary statistics extracted from genome wide association studies of Body Mass Index (BMI) and AD. MR analysis was performed in both directions to establish the direction of causality between BMI and AD. We find that genetically determined increase in adiposity is associated with increased risk of AD (odds ratio of AD 1.08 [95% CI 1.01 to 1.14; p = 0.015] per unit increase in BMI). Conversely, genetically determined increased risk of AD is not associated with a higher BMI (change in BMI attributable to AD based on genetic information: 0.00; 95% CI - 0.02 to 0.02; p = 0.862). There was no evidence for confounding of these genetic analyses by horizontal pleiotropy. Our results indicate that the association of AD with obesity is likely to reflect a causal role for adiposity in the development of AD. Our findings enhance understanding of the etiology of AD, and the basis for experimental studies to evaluate the mechanistic pathways by which adiposity promotes AD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-72301-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7498603PMC
September 2020

Outpatient management of heart valve disease following the COVID-19 pandemic: implications for present and future care.

Heart 2020 10 31;106(20):1549-1554. Epub 2020 Aug 31.

Guy's and Saint Thomas' NHS Foundation Trust, London, London, UK.

The established processes for ensuring safe outpatient surveillance of patients with known heart valve disease (HVD), echocardiography for patients referred with new murmurs and timely delivery of surgical or transcatheter treatment for patients with severe disease have all been significantly impacted by the novel coronavirus pandemic. This has created a large backlog of work and upstaging of disease with consequent increases in risk and cost of treatment and potential for worse long-term outcomes. As countries emerge from lockdown but with COVID-19 endemic in society, precautions remain that restrict 'normal' practice. In this article, we propose a methodology for restructuring services for patients with HVD and provide recommendations pertaining to frequency of follow-up and use of echocardiography at present. It will be almost impossible to practice exactly as we did prior to the pandemic; thus, it is essential to prioritise patients with the greatest clinical need, such as those with symptomatic severe HVD. Local procedural waiting times will need to be considered, in addition to usual clinical characteristics in determining whether patients requiring intervention would be better suited having surgical or transcatheter treatment. We present guidance on the identification of stable patients with HVD that could have follow-up deferred safely and suggest certain patients that could be discharged from follow-up if waiting lists are triaged with appropriate clinical input. Finally, we propose that novel models of working enforced by the pandemic-such as increased use of virtual clinics-should be further developed and evaluated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/heartjnl-2020-317600DOI Listing
October 2020

Impact of arterio-ventricular interaction on first-phase ejection fraction in aortic stenosis.

Eur Heart J Cardiovasc Imaging 2021 05;22(6):650-657

Department of Heart Disease, Haukeland University Hospital, Bergen, Norway.

Aims: First-phase ejection fraction (EF1), the EF at the time to peak aortic jet velocity, has been proposed as a novel marker of peak systolic function in aortic stenosis (AS). This study aimed to explore the association of myocardial contractility and arterial load with EF1 in AS patients.

Methods And Results: Data from a prospective, cross-sectional study of 114 patients with mild, moderate, and severe AS with preserved left ventricular EF (>50%) were analysed. EF1 was measured as the volume change from end-diastole to the time that corresponded to peak aortic jet velocity. Myocardial contractility was assessed by strain rate measured by speckle tracking echocardiography. Arterial stiffness was assessed by central pulse pressure/stroke volume index ratio (PP/SVi). The total study population included 48% women, median age was 73 years, and mean peak aortic jet velocity was 3.47 m/s. In univariable linear regression analyses, lower EF1 was associated with higher age, higher peak aortic jet velocity, lower global EF, lower global longitudinal strain, lower strain rate, and higher PP/SVi. There was no significant association between EF1 and heart rate or sex. In multivariable linear regression analysis, EF1 was associated with lower strain rate and higher PP/SVi, independent of AS severity. Replacing PP/SVi by valvular impedance did not change the results.

Conclusion: In patients with AS, reduced myocardial contractility and increased arterial load were associated with lower EF1 independent of the severity of valve stenosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjci/jeaa154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110316PMC
May 2021

Sudden cardiac death in asymptomatic patients with aortic stenosis.

Heart 2020 11 31;106(21):1646-1650. Epub 2020 Jul 31.

Department of Cardiology and Angiology II, University Heart Center Freiburg / Bad Krozingen, Bad Krozingen, Germany.

Objective: We retrospectively analysed outcome data from the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study to assess the incidence and potential risk factors of sudden cardiac death (SCD) in this prospectively followed cohort of asymptomatic patients with aortic stenosis (AS).

Methods: Of the 1873 patients included in SEAS, 1849 (99%) with mild to moderate AS (jet velocity 2.5-4.0 m/s at baseline) and available clinical, echocardiographic and follow-up data were analysed. Patients undergoing aortic valve replacement were censored at the time of operation.

Results: During an overall follow-up of 46.1±14.6 months, SCD occurred in 27 asymptomatic patients (1.5%) after a mean of 28.3±16.6 months. The annualised event rate was 0.39%/year. The last follow-up echocardiography prior to the event showed mild to moderate stenosis in 22 and severe stenosis (jet velocity >4 m/s) in 5 victims of SCD. The annualised event rate after the diagnosis of severe stenosis was 0.60%/year compared with 0.46%/year in patients who did not progress to severe stenosis (p=0.79). Patients with SCD were older (p=0.01), had a higher left ventricular mass index (LVMI, p=0.001) and had a lower body mass index (BMI, p=0.02) compared with patients surviving follow-up. Cox regression analysis identified age (HR 1.06, 95% CI 1.01 to 1.11 per year, p=0.02), increased LVMI (HR 1.20, 95% CI 1.10 to 1.32 per 10 g/m, p<0.001) and lower BMI (HR 0.87, 95% CI 0.79 to 0.97 per kg/m, p=0.01) as independent risk factors of SCD.

Conclusion: SCD in patients with asymptomatic mild to moderate AS is rare and strongly related to left ventricular hypertrophy but not stenosis severity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/heartjnl-2019-316493DOI Listing
November 2020

Leaflet thrombosis in transcatheter aortic valves implants: a new marker of risk?

Authors:
John B Chambers

Eur Heart J Cardiovasc Imaging 2020 10;21(10):1090-1091

Cardiothoracic Centre, Guy's and St Thomas' Hospitals, Westminster Bridge Road, London SE1 7EH, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjci/jeaa158DOI Listing
October 2020

Epigenomes of Human Hearts Reveal New Genetic Variants Relevant for Cardiac Disease and Phenotype.

Circ Res 2020 08 12;127(6):761-777. Epub 2020 Jun 12.

From the Cardiovascular Research Institute, National University Health System, Singapore (W.L.W.T., C.G.A.-N., E.W., C.J.M.L., H.S.T., A.P., Z.W., B.P., M.I.A., R.S.Y.F.).

Rationale: Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging and requires prohibitively large cohort sizes in genome-wide association studies to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci, elucidated by direct epigenetic profiling of specific human tissues, may contribute toward prioritizing subthreshold variants for disease association.

Objective: Here, we captured noncoding genetic variants by performing epigenetic profiling for enhancer H3K27ac chromatin immunoprecipitation followed by sequencing in 70 human control and end-stage failing hearts.

Methods And Results: We have mapped a comprehensive catalog of 47 321 putative human heart enhancers and promoters. Three thousand eight hundred ninety-seven differential acetylation peaks (FDR [false discovery rate], 5%) pointed to pathways altered in heart failure. To identify cardiac histone acetylation quantitative trait loci (haQTLs), we regressed out confounding factors including heart failure disease status and used the G-SCI (Genotype-independent Signal Correlation and Imbalance) test to call out 1680 haQTLs (FDR, 10%). RNA sequencing performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression quantitative trait loci), either in (180) or through long-range interactions (81), identified by Hi-C (high-throughput chromatin conformation assay) and HiChIP (high-throughput protein centric chromatin) performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of TF (transcription factor)-binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalization of haQTLs with the subthreshold loci of heart-related genome-wide association studies datasets.

Conclusions: Disease and phenotype association for 62 unique loci are now implicated. These loci may indeed mediate their effect through modification of enhancer H3K27 acetylation enrichment and their corresponding gene expression differences (bioRxiv: https://doi.org/10.1101/536763). Graphical Abstract: A graphical abstract is available for this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.120.317254DOI Listing
August 2020

The tricuspid annular plane systolic excursion to systolic pulmonary artery pressure index: Association with all-cause mortality in patients with moderate or severe tricuspid regurgitation.

Int J Cardiol 2020 Oct 5;317:176-180. Epub 2020 Jun 5.

Cardiothoracic Centre, Guy's & St Thomas' NHS Foundation Trust, London, United Kingdom.

Background: In patients with significant tricuspid regurgitation (TR) the conventional markers for the assessment of right ventricular (RV) systolic function may be less accurate. Tricuspid annular plane systolic excursion (TAPSE) indexed to systolic pulmonary artery pressure (SPAP) (TAPSE/SPAP) may be prognostically useful in pulmonary hypertension and left ventricular dysfunction. Our aim was to explore its use in patients with moderate or severe TR.

Methods: A total of 209 patients (72 ± 14 years, 56% women) with moderate (n = 123) or severe (n = 86) TR (primary in 6% and secondary in 94%) were followed up for a median of 80 months (mean 70 ± 33 months). The clinical correlates of TAPSE/SPAP index and association with all-cause mortality were assessed.

Results: The TAPSE/SPAP index was inversely correlated with all-cause mortality with an optimal threshold of 0.49 mm/mmHg. A low index was found in 139 (68%) patients. In a multivariate Cox regression analysis adjusted for age, smoking, coronary artery disease, left ventricular ejection fraction, right atrium area and mitral valve replacement, low TAPSE/SPAP index was associated with significantly higher hazard ratio of all-cause mortality (HR: 2.07; 95% CI 1.32-3.27, p = .002). Age, coronary artery disease, left ventricular ejection fraction and right atrium area were other independent predictors of all-cause mortality.

Conclusion: The TAPSE/SPAP index, reflecting RV systolic function in the longitudinal axis corrected for force generating by the RV is a powerful predictor of all-cause mortality in patients with moderate or severe TR.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ijcard.2020.05.093DOI Listing
October 2020

Identification of type 2 diabetes loci in 433,540 East Asian individuals.

Nature 2020 06 6;582(7811):240-245. Epub 2020 May 6.

Vanderbilt Genetics Institute, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.

Meta-analyses of genome-wide association studies (GWAS) have identified more than 240 loci that are associated with type 2 diabetes (T2D); however, most of these loci have been identified in analyses of individuals with European ancestry. Here, to examine T2D risk in East Asian individuals, we carried out a meta-analysis of GWAS data from 77,418 individuals with T2D and 356,122 healthy control individuals. In the main analysis, we identified 301 distinct association signals at 183 loci, and across T2D association models with and without consideration of body mass index and sex, we identified 61 loci that are newly implicated in predisposition to T2D. Common variants associated with T2D in both East Asian and European populations exhibited strongly correlated effect sizes. Previously undescribed associations include signals in or near GDAP1, PTF1A, SIX3, ALDH2, a microRNA cluster, and genes that affect the differentiation of muscle and adipose cells. At another locus, expression quantitative trait loci at two overlapping T2D signals affect two genes-NKX6-3 and ANK1-in different tissues. Association studies in diverse populations identify additional loci and elucidate disease-associated genes, biology, and pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-020-2263-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7292783PMC
June 2020

High-molecular-weight von Willebrand Factor multimer ratio differentiates true-severe from pseudo-severe classical low-flow, low-gradient aortic stenosis.

Eur Heart J Cardiovasc Imaging 2020 10;21(10):1123-1130

Department of Cardiology, Kepler University Hospital, Medical Faculty Johannes Kepler University Linz, Krankenhausstrasse 9, 4020 Linz, Austria.

Aims: Upon high wall shear stress, high-molecular-weight (HMW) von Willebrand Factor (VWF) multimers are degraded, thus, HMW VWF multimer deficiency mirrors haemodynamics at the site of aortic stenosis (AS). The aim of the present study was to analyse the role of HMW VWF multimer ratio for subcategorization of classical low-flow, low-gradient (LF/LG) AS.

Methods And Results: Eighty-three patients with classical LF/LG AS were prospectively recruited and HMW VWF multimer pattern was analysed using a densitometric quantification of western blot bands. Patients were subclassified into true-severe (TS) and pseudo-severe (PS) classical LF/LG AS based on dobutamine stress echocardiography (DSE). Positive and negative predictive values (PPV/NPV) of HMW VWF multimer ratio for diagnosis of the TS subtype were calculated. HMW VWF multimer ratio in TS classical LF/LG AS was significantly decreased compared to PS classical LF/LG AS (0.86 ± 0.27 vs. 1.06 ± 0.09, P < 0.001). HMW VWF multimer deficiency occurred exclusively in the TS subtype with an optimal PPV of 1.000 and NPV of 0.379. HMW VWF multimer ratio showed a strong correlation with mean transvalvular pressure gradients during DSE (r = -0.616; P < 0.001). HMW VWF multimer ratio measured at baseline was higher compared to levels measured after DSE (0.87 ± 0.27 vs. 0.84 ± 0.31; P = 0.031) indicating DSE-induced increased proteolysis.

Conclusion: HMW VWF multimer ratio represents a valuable biomarker for classical LF/LG AS subclassification and mirrors haemodynamics during DSE. HMW VWF multimer ratio identifies the TS subtype without the use of other imaging techniques.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ehjci/jeaa056DOI Listing
October 2020

Specialist valve clinic in a cardiac centre: 10-year experience.

Open Heart 2020 20;7(1):e001262. Epub 2020 Apr 20.

Guy's and St Thomas' Hospital, London, UK.

Aims: Guidelines recommend specialist valve clinics as best practice for the assessment and conservative management of patients with heart valve disease. However, there is little guidance on how to set up and organise a clinic. The aim of this study is to describe a clinic run by a multidisciplinary team consisting of cardiologists, physiologist/scientists and a nurse.

Methods: The clinical and organisational aims of the clinic, inclusion and exclusion criteria, and links with other services are described. The methods of training non-clinical staff are detailed. Data were prospectively entered onto a database and the study consisted of an analysis of the clinical characteristics and outcomes of all patients seen between 1 January 2009 and 31 December 2018.

Results: There were 2126 new patients and 9522 visits in the 10-year period. The mean age was 64.8 and 55% were male. Of the visits, 3587 (38%) were to the cardiologists, 4092 (43%) to the physiologist/scientists and 1843 (19%) to the nurse. The outcomes from the cardiologist clinics were cardiology follow-up in 460 (30%), referral for surgery in 354 (23%), referral to the physiologist/scientist clinic in 412 (27%) or to the nurse clinic in 65 (4.3%) and discharge in 230 (15%). The cardiologist needed to see 6% from the nurse clinic and 10% from the physiologist/scientist clinic, while advice alone was sufficient in 10% and 9%.

Conclusion: A multidisciplinary specialist valve clinic is feasible and sustainable in the long term.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/openhrt-2020-001262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204551PMC
December 2020
-->