Antithrombotic therapy after heart valve surgery: contemporary practice in the UK.

OBJECTIVES: There is a lack of high-quality data informing the optimal antithrombotic drug strategy following bioprosthetic heart valve replacement or valve repair. Disparity in recommendations from international guidelines reflects this. This study aimed to document current patterns of antithrombotic prescribing after heart valve surgery in the UK. METHODS: All UK consultant cardiac surgeons were e-mailed a custom-designed survey. The use of oral anticoagulant (OAC) and/or antiplatelet drugs following bioprosthetic aortic valve replacement or mitral valve replacement, or mitral valve repair (MVrep), for patients in sinus rhythm, without additional indications for antithrombotic medication, was assessed. Additionally, we evaluated anticoagulant choice following MVrep in patients with atrial fibrillation. RESULTS: We identified 260 UK consultant cardiac surgeons from 36 units, of whom 103 (40%) responded, with 33 units (92%) having at least 1 respondent. The greatest consensus was for patients undergoing bioprosthetic aortic valve replacement, in which 76% of surgeons favour initial antiplatelet therapy and 53% prescribe lifelong treatment. Only 8% recommend initial OAC. After bioprosthetic mitral valve replacement, 48% of surgeons use an initial OAC strategy (versus 42% antiplatelet), with 66% subsequently prescribing lifelong antiplatelet therapy. After MVrep, recommendations were lifelong antiplatelet agent alone (34%) or following 3 months OAC (20%), no antithrombotic agent (20%), or 3 months OAC (16%). After MVrep for patients with established atrial fibrillation, surgeons recommend warfarin (38%), a direct oral anticoagulant (37%) or have no preference between the 2 (25%). CONCLUSIONS: There is considerable variation in the use of antithrombotic drugs after heart valve surgery in the UK and a lack of high-quality evidence to guide practice, underscoring the need for randomized studies.

Chimeric Antigen Receptor T-Cell Access in Patients with Relapsed/Refractory Large B-Cell Lymphoma: Association of Access with Social Determinants of Health and Travel Time to Treatment Centers.

Large B-cell lymphoma (LBCL) is the most common type of non-Hodgkin lymphoma. Chimeric antigen receptor T-cell (CAR T) therapy represents a novel treatment with curative potential for relapsed or refractory (R/R) LBCL, but there are access barriers to this innovative therapy that are not well-studied. (1) Assess the impact of geographic factors and social determinants of health (SDOH) on access to treatment with CAR T in a sample of patients with R/R LBCL and ≥2 prior lines of treatment (LOT). (2) Compare and contrast patient characteristics, SDOH, and travel time between patients with R/R LBCL who received CAR T and those who did not. An observational, nested case-control study of patients with R/R LBCL, ≥2 prior LOT, not in a clinical trial, identified using 100% Medicare Fee-For-Service and national multi-payer claims databases. Patients were linked to near-neighborhood SDOH using 9-digit ZIP-code address. Driving distance and time between residence and nearest CAR T treatment center (TC) was calculated. Patients were stratified based on treatments received upon third LOT initiation (Index Date) or later: (1) received CAR T and (2) did not receive CAR T. Multivariable logistic regression was used to evaluate factors associated with CAR T. About 5011 patients met inclusion criteria, with 628 (12.5%) in the CAR T group. Regression models found the likelihood of receiving CAR T decreased with patient age (odds ratio [OR] = .96, P < .001), and males were 29% more likely to receive CAR T (OR = 1.29, P = .02). Likelihood of CAR T increased with Charlson Comorbidity Index (CCI; OR = 1.07, P < .001) indicating patients with more comorbidities were more likely to receive CAR T. Black patients were less than half as likely to receive CAR T than White patients (OR = .44, P = .01). Asian patients did not significantly differ from White patients (OR = 1.43, P = .24), and there was a trend for Hispanic patients to have a slightly lower likelihood of CAR T (OR = .50, P = .07). Higher household income was associated with receipt of CAR T, with the lowest income group more than 50% less likely to receive CAR T than the highest (OR = .44, P = .002), and the second lowest income group more than 30% less likely (OR = .68, P = .02). Finally, likelihood of CAR T therapy was reduced when the driving time to the nearest TC was 121 to 240 minutes (reference group: ≤30 minutes; OR = .64, P = .04). Travel times between 31 and 121 or greater than 240 minutes were not significantly different from ≤30 minutes. Payer type was collinear with age and could not be included in the regression analysis, but patients with commercial insurance were 1.5 to 3 times more likely to receive CAR T than other payers on an unadjusted basis. We identified significant disparities in access to CAR T related to demographics and SDOH. Patients who were older, female, low income, or Black were less likely to receive CAR T. The positive association of CCI with CAR T requires further research. Given the promising outcomes of CAR T, there is urgent need to address identified disparities and increase efforts to overcome access barriers.

Smokeless and combustible tobacco use among 148,944 South Asian adults: a cross-sectional study of South Asia Biobank.

INTRODUCTION: Tobacco use, in both smoking and smokeless forms, is highly prevalent among South Asian adults. The aims of the study were twofold: (1) describe patterns of SLT and combustible tobacco product use in four South Asian countries stratified by country and sex, and (2) assess the relationships between SLT and smoking intensity, smoking quit attempts, and smoking cessation among South Asian men. METHODS: Data were obtained from South Asia Biobank Study, collected between 2018 and 2022 from 148,944 men and women aged 18 years and above, living in Bangladesh, India, Pakistan, or Sri Lanka. Mixed effects multivariable logistic and linear regression were used to quantify the associations of SLT use with quit attempt, cessation, and intensity. RESULTS: Among the four South Asian countries, Bangladesh has the highest rates of current smoking (39.9% for male, 0.4% for female) and current SLT use (24.7% for male and 23.4% for female). Among male adults, ever SLT use was associated with a higher odds of smoking cessation in Bangladesh (OR, 2.88; 95% CI, 2.65, 3.13), India (OR, 2.02; 95% CI, 1.63, 2.50), and Sri Lanka (OR, 1.36; 95% CI, 1.14, 1.62). Ever SLT use and current SLT use was associated with lower smoking intensity in all countries. CONCLUSIONS: In this large population-based study of South Asian adults, rates of smoking and SLT use vary widely by country and gender. Men who use SLT products are more likely to abstain from smoking compared with those who do not.

Exercise Testing in Aortic Stenosis: Safety, Tolerability, Clinical Benefits and Prognostic Value.

BACKGROUND: Routine exercise testing in asymptomatic patients with valvular heart disease (VHD) better classifies the hemodynamic severity of valve stenosis or regurgitation, and describes the symptomatic status and functional capacity of the patient. This is crucial for planned surveillance and optimal timing of surgery, particularly for aortic stenosis (AS), because once symptoms occur, there is a sharp increase in the risk of sudden death unless valve intervention is performed. PURPOSE: To conduct a focused clinical review on the benefits of exercise testing in patients with AS. METHODS: The electronic database PubMed was systematically searched for relevant retrospective and prospective cohort studies reporting on the safety, feasibility and tolerability of exercise testing in VHD, with a special focus on AS. RESULTS AND CONCLUSIONS: In patients with significant AS, exercise testing is safe, feasible and reveals symptoms in a significant proportion of patients. In addition, serial testing has incremental prognostic value over a baseline test alone. Exercise testing in patients with AS is underused and should be performed routinely to refine the hemodynamic severity of AS.

Real-time diabetic retinopathy screening by deep learning in a multisite national screening programme: a prospective interventional cohort study.

BACKGROUND: Diabetic retinopathy is a leading cause of preventable blindness, especially in low-income and middle-income countries (LMICs). Deep-learning systems have the potential to enhance diabetic retinopathy screenings in these settings, yet prospective studies assessing their usability and performance are scarce. METHODS: We did a prospective interventional cohort study to evaluate the real-world performance and feasibility of deploying a deep-learning system into the health-care system of Thailand. Patients with diabetes and listed on the national diabetes registry, aged 18 years or older, able to have their fundus photograph taken for at least one eye, and due for screening as per the Thai Ministry of Public Health guidelines were eligible for inclusion. Eligible patients were screened with the deep-learning system at nine primary care sites under Thailand's national diabetic retinopathy screening programme. Patients with a previous diagnosis of diabetic macular oedema, severe non-proliferative diabetic retinopathy, or proliferative diabetic retinopathy; previous laser treatment of the retina or retinal surgery; other non-diabetic retinopathy eye disease requiring referral to an ophthalmologist; or inability to have fundus photograph taken of both eyes for any reason were excluded. Deep-learning system-based interpretations of patient fundus images and referral recommendations were provided in real time. As a safety mechanism, regional retina specialists over-read each image. Performance of the deep-learning system (accuracy, sensitivity, specificity, positive predictive value [PPV], and negative predictive value [NPV]) were measured against an adjudicated reference standard, provided by fellowship-trained retina specialists. This study is registered with the Thai national clinical trials registry, TCRT20190902002. FINDINGS: Between Dec 12, 2018, and March 29, 2020, 7940 patients were screened for inclusion. 7651 (96·3%) patients were eligible for study analysis, and 2412 (31·5%) patients were referred for diabetic retinopathy, diabetic macular oedema, ungradable images, or low visual acuity. For vision-threatening diabetic retinopathy, the deep-learning system had an accuracy of 94·7% (95% CI 93·0-96·2), sensitivity of 91·4% (87·1-95·0), and specificity of 95·4% (94·1-96·7). The retina specialist over-readers had an accuracy of 93·5 (91·7-95·0; p=0·17), a sensitivity of 84·8% (79·4-90·0; p=0·024), and specificity of 95·5% (94·1-96·7; p=0·98). The PPV for the deep-learning system was 79·2 (95% CI 73·8-84·3) compared with 75·6 (69·8-81·1) for the over-readers. The NPV for the deep-learning system was 95·5 (92·8-97·9) compared with 92·4 (89·3-95·5) for the over-readers. INTERPRETATION: A deep-learning system can deliver real-time diabetic retinopathy detection capability similar to retina specialists in community-based screening settings. Socioenvironmental factors and workflows must be taken into consideration when implementing a deep-learning system within a large-scale screening programme in LMICs. FUNDING: Google and Rajavithi Hospital, Bangkok, Thailand. TRANSLATION: For the Thai translation of the abstract see Supplementary Materials section.

The iHealth-T2D study, prevention of type 2 diabetes amongst South Asians with central obesity and prediabetes: study protocol for a randomised controlled trial.

BACKGROUND: People from South Asia are at increased risk of type 2 diabetes (T2D). There is an urgent need to develop approaches for the prevention of T2D in South Asians that are cost-effective, generalisable and scalable across settings. HYPOTHESIS: Compared to usual care, the risk of T2D can be reduced amongst South Asians with central obesity or raised HbA1c, through a 12-month lifestyle modification programme delivered by community health workers. DESIGN: Cluster randomised clinical trial (1:1 allocation to intervention or usual care), carried out in India, Pakistan, Sri Lanka and the UK, with 30 sites per country (120 sites total). Target recruitment 3600 (30 participants per site) with annual follow-up for 3 years. ENTRY CRITERIA: South Asian, men or women, age 40-70 years with (i) central obesity (waist circumference ≥ 100 cm in India and Pakistan; ≥90 cm in Sri Lanka) and/or (ii) prediabetes (HbA1c 6.0-6.4% inclusive). EXCLUSION CRITERIA: known type 1 or 2 diabetes, normal or underweight (body mass index < 22 kg/m2); pregnant or planning pregnancy; unstable residence or planning to leave the area; and serious illness. ENDPOINTS: The primary endpoint is new-onset T2D at 3 years, defined as (i) HbA1c ≥ 6.5% or (ii) physician diagnosis and on treatment for T2D. Secondary endpoints at 1 and 3 years are the following: (i) physical measures: waist circumference, weight and blood pressure; (ii) lifestyle measures: smoking status, alcohol intake, physical activity and dietary intake; (iii) biochemical measures: fasting glucose, insulin and lipids (total and HDL cholesterol, triglycerides); and (iv) treatment compliance. INTERVENTION: Lifestyle intervention (60 sites) or usual care (60 sites). Lifestyle intervention was delivered by a trained community health worker over 12 months (5 one-one sessions, 4 group sessions, 13 telephone sessions) with the goal of the participants achieving a 7% reduction in body mass index and a 10-cm reduction in waist circumference through (i) improved diet and (ii) increased physical activity. Usual care comprised a single 30-min session of lifestyle modification advice from the community health worker. RESULTS: We screened 33,212 people for inclusion into the study. We identified 10,930 people who met study entry criteria, amongst whom 3682 agreed to take part in the intervention. Study participants are 49.2% female and aged 52.8 (SD 8.2) years. Clinical characteristics are well balanced between intervention and usual care sites. More than 90% of follow-up visits are scheduled to be complete in December 2020. Based on the follow-up to end 2019, the observed incidence of T2D in the study population is in line with expectations (6.1% per annum). CONCLUSION: The iHealth-T2D study will advance understanding of strategies for the prevention of diabetes amongst South Asians, use approaches for screening and intervention that are adapted for low-resource settings. Our study will thus inform the implementation of strategies for improving the health and well-being of this major global ethnic group. IRB APPROVAL: 16/WM/0171 TRIAL REGISTRATION: EudraCT 2016-001350-18 . Registered on 14 April 2016. ClinicalTrials.gov NCT02949739 . Registered on 31 October 2016, First posted on 31/10/2016.

Left atrial volume index predicts adverse events in asymptomatic moderate or severe aortic stenosis.

OBJECTIVE: In aortic stenosis (AS), chronic pressure overload on left ventricle (LV) leads to LV hypertrophy, impaired relaxation, increased chamber stiffness, fibrosis and left atrial (LA) dilatation. An enlarged LA may be a marker of longstanding diastolic dysfunction (DD) and more advanced disease in AS. We aimed to assess the impact of LA volume index (LAVI) on events in patients with moderate or severe AS. METHODS: A total of 324 patients (mean age 69 ± 13 years, 61% men) were included. LA volume was measured by biplane Simpson's method using apical four- and two-chamber views and indexed to body surface area. An increased LAVI was defined as > 34 ml/m2 . RESULTS: The mean EF was 64 ± 8%, LAVI 35 ± 14 ml/m2 and flow rate 244 ± 70 ml/s. The number of total events was 275 (85%): 243 (75%) aortic valve replacement and 32 (10%) deaths. Mean follow-up 23.7 ± 23.8 months (median 15.2 months). An increased LAVI (45% [n = 145]) was associated with adverse events (HR 1.86; 95% CI 1.24-2.82, p = 0.003) independent of age, smoking, diabetes, atrial fibrillation, LV ejection fraction, LV mass, aortic valve area, and low flow rate (<200 ml/s). In the same multivariate model, when increased LAVI was replaced by E/e' ratio ≥14 cm, no association was found between E/e' ratio ≥14 cm and adverse events (HR 1.18; 95% CI .78-1.78, p = 0.430). CONCLUSION: LAVI was an independent predictor of adverse events in patients with moderate or severe AS and preserved ejection fraction. Including LAVI in the risk assessment of AS patients may further improve risk stratification.

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

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.

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.

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.

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.

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.

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

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.

Determinants and prognostic value of echocardiographic first-phase ejection fraction in aortic stenosis.

OBJECTIVE: First-phase ejection fraction (EF1) is a novel measure of early left ventricular systolic dysfunction. We investigated determinants of EF1 and its prognostic value in aortic stenosis. METHODS: EF1 was measured retrospectively in participants of an echocardiography/cardiovascular magnetic resonance cohort study which recruited patients with aortic stenosis (peak aortic velocity of ≥2 m/s) between 2012 and 2014. Linear regression models were constructed to examine variables associated with EF1. Cox proportional hazards were used to determine the prognostic power of EF1 for aortic valve replacement (AVR, performed as part of clinical care in accordance with international guidelines) or death. RESULTS: Total follow-up of the 149 participants (69.8% male, 70 (65-76) years, mean gradient 33 (21-42) mm Hg) was 238 029 person-days. Sixty-seven participants (45%) had a low baseline EF1 (<25%) despite normal ejection fraction (67% (62%-71%)). Patients with low EF1 had more severe aortic stenosis (mean gradient 39 (34-45) mm Hg vs 24 (16-35) mm Hg, p<0.001) and more myocardial fibrosis (indexed extracellular volume (iECV) (24.2 (19.6-28.7) mL/m2 vs 20.6 (16.8-24.3) mL/m2, p=0.002; late gadolinium enhancement (LGE) prevalence 52% vs 20%, p<0.001). Zva, iECV and infarct LGE were independent predictors of EF1. EF1 improved post-AVR (n=57 with post-AVR EF1 available, baseline 16 (12-24) vs follow-up 27% (22%-31%); p<0.001). Low baseline EF1 was an independent predictor of AVR/death (HR 5.6, 95% CI 3.4 to 9.4), driven by AVR. CONCLUSION: EF1 quantifies early, potentially reversible systolic dysfunction in aortic stenosis, is associated with global afterload and myocardial fibrosis, and is an independent predictor of AVR.

Sex differences in aortic stenosis: from pathophysiology to treatment.

Introduction: In aortic stenosis (AS), there are clear sex differences in clinical presentation, left ventricular (LV) response to pressure overload, and pathophysiology of valvular calcification. These differences may affect outcome following valve intervention.Area covered: This review aims to discuss sex differences in clinical presentation, pathophysiology of aortic valve calcification, LV remodeling in view of historic and recent echocardiographic and cardiac magnetic resonance imaging studies, and outcome after valve intervention. In addition, it will also provide some brief insights on the exercise physiology in women and men with AS.Expert commentary: Women at presentation are often older, have higher prevalence of hypertension and diastolic dysfunction, while men are younger, and more often have a bicuspid aortic valve and higher atherosclerotic disease burden. Men have more valve calcification than women for a given severity of AS and develop different patterns of LV remodeling and myocardial fibrosis. Although women tend to walk shorter on treadmill and achieve lower metabolic equivalents, they achieve similar peak heart rates and blood pressure, and the frequency of revealed symptoms during exercise test is comparable in both sexes. Men are more likely to undergo a surgical AVR with better outcome, while women have generally better outcome after TAVI.

Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci.

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Impact of pulmonary hypertension on outcome in patients with moderate or severe tricuspid regurgitation.

Objectives: The true prevalence and disease burden of moderate or severe (significant) tricuspid regurgitation (TR) in patients undergoing routine echocardiography remains unknown. Our aim was to explore the prevalence of significant TR and the impact of pulmonary hypertension (PH) on outcome in a less selected cohort of patients referred to echocardiography. Methods: From 12 791 echocardiograms performed between January and December 2010, a total of 209 (1.6%) patients (72±14 years, 56% men) were identified with significant TR; 123 (0.96%) with moderate and 86 (0.67%) with severe TR. Median follow-up time was 80 months (mean 70±33 months). Systolic pulmonary artery pressure was derived from peak velocity of tricuspid regurgitant jet plus the right atrial pressure and considered elevated if ≥40 mm Hg (PH). Results: During follow-up there were 123 (59%) deaths with no difference in mortality between moderate and severe TR (p=0.456). The death rates were 93 (67%) in patients with PH versus 30 (42%) without PH (p<0.001). PH was associated with lower event-free survival in moderate (log-rank, p<0.001), but not in severe TR (log-rank, p=0.133). In a multivariate Cox regression analysis adjusted for age, smoking, coronary artery disease, reduced right ventricle S', lower left ventricular ejection fraction at baseline, right atrium size and mitral valve replacement, PH remained a significant predictor of all-cause mortality (HR 2.22; 95% CI 1.41 to 3.47, p=0.001). Conclusions: Moderate or severe TR was found in 1.6% of patients attending for routine echocardiograms. PH identified a high-risk subset of patients with moderate TR but not with severe TR.

Target genes, variants, tissues and transcriptional pathways influencing human serum urate levels.

Elevated serum urate levels cause gout and correlate with cardiometabolic diseases via poorly understood mechanisms. We performed a trans-ancestry genome-wide association study of serum urate in 457,690 individuals, identifying 183 loci (147 previously unknown) that improve the prediction of gout in an independent cohort of 334,880 individuals. Serum urate showed significant genetic correlations with many cardiometabolic traits, with genetic causality analyses supporting a substantial role for pleiotropy. Enrichment analysis, fine-mapping of urate-associated loci and colocalization with gene expression in 47 tissues implicated the kidney and liver as the main target organs and prioritized potentially causal genes and variants, including the transcriptional master regulators in the liver and kidney, HNF1A and HNF4A. Experimental validation showed that HNF4A transactivated the promoter of ABCG2, encoding a major urate transporter, in kidney cells, and that HNF4A p.Thr139Ile is a functional variant. Transcriptional coregulation within and across organs may be a general mechanism underlying the observed pleiotropy between urate and cardiometabolic traits.

Epigenome-Wide Association Study of Incident Type 2 Diabetes in a British Population: EPIC-Norfolk Study.

Epigenetic changes may contribute substantially to risks of diseases of aging. Previous studies reported seven methylation variable positions (MVPs) robustly associated with incident type 2 diabetes mellitus (T2DM). However, their causal roles in T2DM are unclear. In an incident T2DM case-cohort study nested within the population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk cohort, we used whole blood DNA collected at baseline, up to 11 years before T2DM onset, to investigate the role of methylation in the etiology of T2DM. We identified 15 novel MVPs with robust associations with incident T2DM and robustly confirmed three MVPs identified previously (near to TXNIP, ABCG1, and SREBF1). All 18 MVPs showed directionally consistent associations with incident and prevalent T2DM in independent studies. Further conditional analyses suggested that the identified epigenetic signals appear related to T2DM via glucose and obesity-related pathways acting before the collection of baseline samples. We integrated genome-wide genetic data to identify methylation-associated quantitative trait loci robustly associated with 16 of the 18 MVPs and found one MVP, cg00574958 at CPT1A, with a possible direct causal role in T2DM. None of the implicated genes were previously highlighted by genetic association studies, suggesting that DNA methylation studies may reveal novel biological mechanisms involved in tissue responses to glycemia.

EDUCATIONAL SERIES ON THE SPECIALIST VALVE CLINIC: How to run a specialist valve clinic: the history, examination and exercise test.

Echocardiography is the key to the detection and initial assessment of valve disease. The examination helps differentiate severe from moderate disease if this is unclear from the echocardiogram, but is less useful than echocardiography for surveillance. However, the history is extremely important because symptoms are an indication for surgery in all types of valve disease. In aortic stenosis, the mortality rises soon after the onset of exertional breathlessness or chest tightness. Exercise testing is an extension of the history and may reveal symptoms in apparently asymptomatic patients. This article discusses the history, examination and exercise testing in patients either newly referred or under routine follow-up in a specialist valve clinic.

Echocardiography and monitoring patients receiving dopamine agonist therapy for hyperprolactinaemia: a joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology.

This is a joint position statement of the British Society of Echocardiography, the British Heart Valve Society and the Society for Endocrinology on the role of echocardiography in monitoring patients receiving dopamine agonist (DA) therapy for hyperprolactinaemia. (1) Evidence that DA pharmacotherapy causes abnormal valve morphology and dysfunction at doses used in the management of hyperprolactinaemia is extremely limited. Evidence of clinically significant valve pathology is absent, except for isolated case reports around which questions remain. (2) Attributing change in degree of valvular regurgitation, especially in mild and moderate tricuspid regurgitation, to adverse effects of DA in hyperprolactinaemia should be avoided if there are no associated pathological changes in leaflet thickness, restriction or retraction. It must be noted that even where morphological change in leaflet structure and function may be suspected, grading is semi-quantitative on echocardiography and may vary between different machines, ultrasound settings and operators. (3) Decisions regarding discontinuation of medication should only be made after review of serial imaging by an echocardiographer experienced in analysing drug-induced valvulopathy or carcinoid heart disease. (4) A standard transthoracic echocardiogram should be performed before a patient starts DA therapy for hyperprolactinaemia. Repeat transthoracic echocardiography should then be performed at 5 years after starting cabergoline in patients taking a total weekly dose less than or equal to 2 mg. If there has been no change on the 5-year scan, repeat echocardiography could continue at 5-yearly intervals. If a patient is taking more than a total weekly dose of 2 mg, then annual echocardiography is recommended.