Publications
888 results found
Kanoni S, Graham SE, Wang Y, et al., 2022, Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis., Genome Biol, Vol: 23
BACKGROUND: Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery. RESULTS: To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N = 1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism. CONCLUSIONS: Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
Kulkarni S, Glover M, Kapil V, et al., 2022, Management of hypertensive crisis: British and Irish Hypertension Society Position document, JOURNAL OF HUMAN HYPERTENSION, ISSN: 0950-9240
Nazarzadeh M, Bidel Z, Canoy D, et al., 2022, Blood pressure-lowering treatment for prevention of major cardiovascular diseases in people with and without type 2 diabetes: an individual participant-level data meta-analysis, The Lancet Diabetes and Endocrinology, Vol: 10, Pages: 645-654, ISSN: 2213-8595
BACKGROUND: Controversy exists as to whether the threshold for blood pressure-lowering treatment should differ between people with and without type 2 diabetes. We aimed to investigate the effects of blood pressure-lowering treatment on the risk of major cardiovascular events by type 2 diabetes status, as well as by baseline levels of systolic blood pressure. METHODS: We conducted a one-stage individual participant-level data meta-analysis of major randomised controlled trials using the Blood Pressure Lowering Treatment Trialists' Collaboration dataset. Trials with information on type 2 diabetes status at baseline were eligible if they compared blood pressure-lowering medications versus placebo or other classes of blood pressure-lowering medications, or an intensive versus a standard blood pressure-lowering strategy, and reported at least 1000 persons-years of follow-up in each group. Trials exclusively on participants with heart failure or with short-term therapies and acute myocardial infarction or other acute settings were excluded. We expressed treatment effect per 5 mm Hg reduction in systolic blood pressure on the risk of developing a major cardiovascular event as the primary outcome, defined as the first occurrence of fatal or non-fatal stroke or cerebrovascular disease, fatal or non-fatal ischaemic heart disease, or heart failure causing death or requiring hospitalisation. Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios (HRs) separately by type 2 diabetes status at baseline, with further stratification by baseline categories of systolic blood pressure (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg). To estimate absolute risk reductions, we used a Poisson regression model over the follow-up duration. The effect of each of the five major blood pressure-lowering drug classes, including angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, β blockers, calcium channel blockers, and th
Fagundes A, Morrow DA, Oyama K, et al., 2022, Biomarker Prediction of Complex Coronary Revascularization Procedures in the FOURIER Trial, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, Vol: 80, Pages: 887-897, ISSN: 0735-1097
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- Citations: 1
Ramdas S, Judd J, Graham SE, et al., 2022, A multi-layer functional genomic analysis to understand noncoding genetic variation in lipids, AMERICAN JOURNAL OF HUMAN GENETICS, Vol: 109, Pages: 1366-1387, ISSN: 0002-9297
Oggero S, Godec T, van Gorp R, et al., 2022, Role of plasma extracellular vesicles in prediction of cardiovascular risk and alterations in response to statin therapy in hypertensive patients., Journal of Hypertension, Vol: 40, ISSN: 0263-6352
BACKGROUND: Rapid and accurate new biomarkers to predict risk of cardiovascular disease (CVD) are essential. The utility of extracellular vesicles in predicting the CVD risk is postulated, yet it remains unknown whether their expression is altered in response to statin therapy. METHODS: We performed in-vitro studies with human umbilical vein endothelial cells (HUVEC) and vascular smooth muscle cells (hVSMC), and conducted a nested case-control study (nCCS) in hypertensive patients (n = 40) randomized to either atorvastatin or placebo in the ASCOT-LLA. Cases had a major adverse cardiovascular event or death (MACE) during 3.5 years of follow-up (median) from the time of extracellular vesicle characterization while controls, matched for age and duration of treatment, remained event-free. Conditional logistic regression models determined the risk of MACE. Additionally, the relationship of extracellular vesicle levels with statin therapy was assessed. RESULTS: Added to HUVEC, extracellular vesicles increased neutrophil recruitment, and to hVSMC, aggravated calcification and proliferation. In the nCCS, compared with controls, cases (i.e. with MACE) had preceding higher levels of CD14+ and CD14+/CD41+ extracellular vesicles (P = 0.009 and P = 0.012, respectively) and a significant reduction in the median size of the vesicles (P = 0.037). On matched analysis, higher CD14+ extracellular vesicles were associated with a 3.7-fold increased risk of MACE (P = 0.032). Patients treated with atorvastatin (vs. placebo) had both reduced size of extracellular vesicles and the proportion of CD146+ extracellular vesicles (P = 0.034 and P = 0.020, respectively). CONCLUSION AND RELEVANCE: These pilot analyses suggest a mechanistic role for extracellular vesicles in the development of CVD, with significant and differential changes in extracellular vesicles amongst those at risk of MACE, and those on atorvastatin therapy.
Rastogi T, Ho FK, Rossignol P, et al., 2022, Comparing and contrasting risk factors for heart failure in patients with and without history of myocardial infarction: data from HOMAGE and the UK Biobank, EUROPEAN JOURNAL OF HEART FAILURE, Vol: 24, Pages: 976-984, ISSN: 1388-9842
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- Citations: 2
Cappuccio FP, Campbell NRC, He FJ, et al., 2022, Sodium and Health: Old Myths and a Controversy Based on Denial, CURRENT NUTRITION REPORTS, Vol: 11, Pages: 172-184
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- Citations: 12
Korthauer LE, Giugliano RP, Guo J, et al., 2022, No association between APOE genotype and lipid lowering with cognitive function in a randomized controlled trial of evolocumab, PLOS ONE, Vol: 17, ISSN: 1932-6203
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- Citations: 2
Sever PP, 2022, Nocebo affects after COVID-19 vaccination, The Lancet Regional Health - Europe, Vol: 12, Pages: 1-2, ISSN: 2666-7762
Oyama K, Giugliano RP, Tang M, et al., 2021, Effect of evolocumab on acute arterial events across all vascular territories : results from the FOURIER trial, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 4821-4829, ISSN: 0195-668X
Graham SE, Clarke SL, Wu K-HH, et al., 2021, The power of genetic diversity in genome-wide association studies of lipids, NATURE, Vol: 600, Pages: 675-+, ISSN: 0028-0836
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- Citations: 60
Marston NA, Giugliano RP, Park J-G, et al., 2021, Cardiovascular Benefit of Lowering Low-Density Lipoprotein Cholesterol Below 40 mg/dL, CIRCULATION, Vol: 144, Pages: 1732-1734, ISSN: 0009-7322
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- Citations: 4
Mujaj B, Zhang Z-Y, Yang W-Y, et al., 2021, Aspirin use is associated with increased risk for incident heart failure: a patient-level pooled analysis, ESC HEART FAILURE, Vol: 9, Pages: 685-694, ISSN: 2055-5822
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- Citations: 3
Keech AC, Oyama K, Sever PS, et al., 2021, Efficacy and Safety of Long-Term Evolocumab Use Among Asian Subjects - A Subgroup Analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) Trial -, CIRCULATION JOURNAL, Vol: 85, Pages: 2063-+, ISSN: 1346-9843
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- Citations: 8
Marston NA, Giugliano RP, Park JG, et al., 2021, Cardiovascular benefit of lowering LDL-C below 1 mmol/L (40 mg/dl), Publisher: OXFORD UNIV PRESS, Pages: 2585-2585, ISSN: 0195-668X
Oyama K, Giugliano R, Tang M, et al., 2021, Acute arterial events across all vascular territories in the FOURIER trial, Publisher: OXFORD UNIV PRESS, Pages: 2947-2947, ISSN: 0195-668X
Whiteley WN, Gupta AK, Godec T, et al., 2021, Long-Term Incidence of Stroke and Dementia in ASCOT, STROKE, Vol: 52, Pages: 3088-3096, ISSN: 0039-2499
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- Citations: 2
Ratneswaren A, Shah ASV, Thom SA, et al., 2021, Tissue Doppler E prime velocity and E/E prime predict 19-year cardiovascular mortality in hypertension, Publisher: OXFORD UNIV PRESS, Pages: 2336-2336, ISSN: 0195-668X
Howard J, Wood F, Finegold J, et al., 2021, Side effect patterns in a crossover trial of statin, placebo and no treatment, Journal of the American College of Cardiology, Vol: 78, Pages: 1210-1222, ISSN: 0735-1097
BackgroundMost people who begin statins abandon them, most commonly because of side-effects. ObjectivesAssess daily symptom scores on statin, placebo and no treatment in participants who had abandoned statins.MethodsParticipants received 12 one-month medication bottles, 4 containing atorvastatin 20mg, 4 placebo and 4 empty. We measured daily symptom intensity for each using an app (scale 1-100). We also measured the nocebo ratio: the ratio of symptoms induced by taking statin that was also induced by taking placebo. Results60 participants were randomized and 49 completed the 12-month protocol. Mean symptom score was 8.0 (95% confidence interval 4.7 to 11.3) in no-tablet months. It was higher in statin months (16.3, 13.0 to 19.6, p<0.001), but also in placebo months (15.4, 12.1 to 18.7, p<0.001), with no difference between the two (p=0.388). The corresponding nocebo ratio was 0.90.In the individual-patient daily data, neither symptom intensity on starting (odds ratio 1.02, 95% CI 0.98 to 1.06, p=0.28) nor extent of symptom relief on stopping (1.01, 95% CI 0.98 to 1.05, p=0.48) distinguished between statin and placebo.Stopping was no more frequent for statin than placebo (p=0.173), and subsequent symptom relief was similar between statin and placebo.6 months after the trial, 30/60 (50%) of participants were back taking statins. ConclusionsThe majority of symptoms caused by statin tablets were nocebo. Clinicians should not interpret symptom intensity or timing of symptom onset or offset (on starting or stopping statin tablets) as indicating pharmacological causation, because the pattern is identical for placebo.
Rahimi K, Bidel Z, Nazarzadeh M, et al., 2021, Age-stratified and blood-pressure-stratified effects of blood-pressure-lowering pharmacotherapy for the prevention of cardiovascular disease and death: an individual participant-level data meta-analysis, The Lancet, Vol: 398, Pages: 1053-1064, ISSN: 0140-6736
BackgroundThe effects of pharmacological blood-pressure-lowering on cardiovascular outcomes in individuals aged 70 years and older, particularly when blood pressure is not substantially increased, is uncertain. We compared the effects of blood-pressure-lowering treatment on the risk of major cardiovascular events in groups of patients stratified by age and blood pressure at baseline.MethodsWe did a meta-analysis using individual participant-level data from randomised controlled trials of pharmacological blood-pressure-lowering versus placebo or other classes of blood-pressure-lowering medications, or between more versus less intensive treatment strategies, which had at least 1000 persons-years of follow-up in each treatment group. Participants with previous history of heart failure were excluded. Data were obtained from the Blood Pressure Lowering Treatment Triallists' Collaboration. We pooled the data and categorised participants into baseline age groups (<55 years, 55–64 years, 65–74 years, 75–84 years, and ≥85 years) and blood pressure categories (in 10 mm Hg increments from <120 mm Hg to ≥170 mm Hg systolic blood pressure and from <70 mm Hg to ≥110 mm Hg diastolic). We used a fixed effects one-stage approach and applied Cox proportional hazard models, stratified by trial, to analyse the data. The primary outcome was defined as either a composite of fatal or non-fatal stroke, fatal or non-fatal myocardial infarction or ischaemic heart disease, or heart failure causing death or requiring hospital admission.FindingsWe included data from 358 707 participants from 51 randomised clinical trials. The age of participants at randomisation ranged from 21 years to 105 years (median 65 years [IQR 59–75]), with 42 960 (12·0%) participants younger than 55 years, 128 437 (35·8%) aged 55–64 years, 128 506 (35·8%) 65–74 years, 54 016 (15·1%) 75–84 years, and
Sever P, Gouni-Berthold I, Keech A, et al., 2021, LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial., European Journal of Preventive Cardiology, Vol: 28, Pages: 805-812, ISSN: 2047-4873
AIMS: Some trials have reported diminished efficacy for statins in the elderly, and in women compared with men. We examined the efficacy and safety of evolocumab by patient age and sex in the FOURIER trial, the first major cardiovascular outcome trial of a PCSK9 inhibitor. METHODS AND RESULTS: FOURIER was a randomised, double blind trial, comparing evolocumab with placebo in 27,564 patients with atherosclerotic cardiovascular disease receiving statin therapy (median follow-up 2.2 years). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation. Cox proportional hazards models were used to assess the efficacy of evolocumab versus placebo stratified by quartiles of patient age and by sex. There were small variations in the cardiovascular event rate across the age range (for the primary endpoint, Kaplan-Meier at 3 years 15.6%, >69 years, vs. 15.1%, ≤56 years, P = 0.45); however, the relative efficacy of evolocumab was consistent regardless of patient age (for the primary endpoint (Q1 hazard ratio, 95% confidence interval) 0.83, 0.72-0.96, Q2 0.88, 0.76-1.01, Q3 0.82, 0.71-0.95, Q4 0.86, 0.74-1.00; Pinteraction = 0.91), and the key secondary endpoint (cardiovascular death, myocardial infarction, stroke) (Q1 0.74 (0.61-0.89), Q2 0.83 (0.69-1.00), Q3 0.78 (0.65-0.94), Q4 0.82 (0.69-0.98)); Pinteraction = 0.81). Women had a lower primary endpoint rate than men (Kaplan-Meier at 3 years 12.5 vs. 15.3%, respectively, P < 0.001). Relative risk reductions in the primary endpoint and key secondary endpoint were similar in women (0.81 (0.69-0.95) and 0.74 (0.61-0.90), respectively) compared with men (0.86 (0.80-0.94) and 0.81 (0.73-0.90), respectively), Pinteraction = 0.48 and 0.44, respectively. Adverse events were more common in women and with increasing age but, with the exception of injection site reactions, ther
Sever P, Gouni-Berthold I, Keech A, et al., 2021, LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial., Eur J Prev Cardiol, Vol: 28, Pages: 805-812
AIMS: Some trials have reported diminished efficacy for statins in the elderly, and in women compared with men. We examined the efficacy and safety of evolocumab by patient age and sex in the FOURIER trial, the first major cardiovascular outcome trial of a PCSK9 inhibitor. METHODS AND RESULTS: FOURIER was a randomised, double blind trial, comparing evolocumab with placebo in 27,564 patients with atherosclerotic cardiovascular disease receiving statin therapy (median follow-up 2.2 years). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation. Cox proportional hazards models were used to assess the efficacy of evolocumab versus placebo stratified by quartiles of patient age and by sex. There were small variations in the cardiovascular event rate across the age range (for the primary endpoint, Kaplan-Meier at 3 years 15.6%, >69 years, vs. 15.1%, ≤56 years, P = 0.45); however, the relative efficacy of evolocumab was consistent regardless of patient age (for the primary endpoint (Q1 hazard ratio, 95% confidence interval) 0.83, 0.72-0.96, Q2 0.88, 0.76-1.01, Q3 0.82, 0.71-0.95, Q4 0.86, 0.74-1.00; Pinteraction = 0.91), and the key secondary endpoint (cardiovascular death, myocardial infarction, stroke) (Q1 0.74 (0.61-0.89), Q2 0.83 (0.69-1.00), Q3 0.78 (0.65-0.94), Q4 0.82 (0.69-0.98)); Pinteraction = 0.81). Women had a lower primary endpoint rate than men (Kaplan-Meier at 3 years 12.5 vs. 15.3%, respectively, P < 0.001). Relative risk reductions in the primary endpoint and key secondary endpoint were similar in women (0.81 (0.69-0.95) and 0.74 (0.61-0.90), respectively) compared with men (0.86 (0.80-0.94) and 0.81 (0.73-0.90), respectively), Pinteraction = 0.48 and 0.44, respectively. Adverse events were more common in women and with increasing age but, with the exception of injection site reactions, ther
Marston NA, Oyama K, Jarolim P, et al., 2021, Combining High-Sensitivity Troponin With the American Heart Association/American College of Cardiology Cholesterol Guidelines to Guide Evolocumab Therapy, CIRCULATION, Vol: 144, Pages: 249-251, ISSN: 0009-7322
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- Citations: 2
Gencer B, Mach F, Murphy SA, 2021, Efficacy of Evolocumab on Cardiovascular Outcomes in Patients With Recent Myocardial Infarction: A Prespecified Secondary Analysis From the FOURIER Trial (vol 5, pg 952, 2020), JAMA CARDIOLOGY, Vol: 6, Pages: 980-980, ISSN: 2380-6583
Messerli FH, Brguljan J, Rexhaj E, et al., 2021, Lowering systolic blood pressure to 120 mmHg or The Lancet's true grit: Epilogue, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 2059-2059, ISSN: 0195-668X
Messerli FH, Brguljan J, Rexhaj E, et al., 2021, Lowering systolic blood pressure to 120 mmHg or The Lancet's true grit, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 2052-2059, ISSN: 0195-668X
Sever P, Pocock S, 2021, 'Lowering systolic blood pressure to 120 mmHg or The Lancet's true grit': Response, EUROPEAN HEART JOURNAL, Vol: 42, Pages: 2055-2056, ISSN: 0195-668X
Chen J, Spracklen CN, Marenne G, et al., 2021, The trans-ancestral genomic architecture of glycemic traits, Nature Genetics, Vol: 53, Pages: 840-860, ISSN: 1061-4036
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 × 10−8), 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.
Fagundes A, Morrow D, Oyama K, et al., 2021, BIOMARKER PREDICTION OF MAJOR CORONARY EVENTS AND COMPLEX REVASCULARIZATION PROCEDURES IN PATIENTS WITH STABLE ATHEROSCLEROSIS, 70th Annual Scientific Session and Expo of the American-College-of-Cardiology (ACC), Publisher: ELSEVIER SCIENCE INC, Pages: 2-2, ISSN: 0735-1097
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