London Life Sciences Prospective Population Research Articles

All-cause, cancer and cardiovascular mortality among South Asians living in the UK: Follow-up of the London Life Sciences Population (LOLIPOP) cohort

Abstract Background Although South Asians are the largest ethnic minority group in the UK, and the largest ethnic group worldwide, few studies have investigated patterns of mortality in South Asians. Methods We investigated 16,391 South Asian and 6,970 European men and women living in the UK, and participating in the London Life Sciences Prospective Population study. Participants were recruited in 2002-2008, and survival determined to 2019. We examined relationships of clinical, anthropometric, and lifestyle risk factors to mortality outcomes. Findings: Compared to Europeans, South Asians had higher prevalence of diabetes, cardiovascular disease, and hypertension, higher waist-hip ratio, fasting glucose, insulin and triglycerides, but lower smoking rates and HDL cholesterol (all P<0.001). Age and sex adjusted all-cause mortality was lower (Hazard Ratio (HR): 0.75 [0.68-0.81], P<0.001), all-cancer mortality was lower (HR 0.50 [0.43-0.58], P<0.001), and coronary heart disease (CHD) mortality was higher (HR 1.29 [1.05-1.60], P<0.01) in South Asians compared to Europeans. Mortality rates were ~50% lower for 9 of the 10 most common cancers in South Asians. After adjusting for risk factors, ethnic differences were attenuated only for CHD mortality. Interpretation: All-cause and cancer mortality are lower, but CHD mortality is higher, in South Asians compared to Europeans. Measured risk factors do not explain lower all-cause and all-cancer mortality, but do account for higher CHD mortality. Our findings provide evidence for population-specific exposures protective against cancers in South Asians, as well as the motivation to further improve cardiovascular risk reduction in this major ethnic group.

Sex, racial differences and healthy aging in normative reference ranges on diastolic function in Ethnic Asians: 2016 ASE guideline revisited

Diastolic dysfunction (DD) has shown to be a hallmark pathological intermediate in the development of heart failure with preserved ejection fraction (HFpEF). We aim to establish age- and sex-stratified normal reference values of diastolic indices and to explore racial-differences. We explored age- and sex-related structural/functional alterations from 6023 healthy ethnic Asians (47.1±10.9 years, 61.3% men) according to 2016 American Society of Echocardiography (ASE) diastolic dysfunction (DD) criteria. Racial comparisons were made using data from London Life Sciences Prospective Population (LOLIPOP) study. Age- and sex-based normative ranges (including mean, median, 10% and 90% lower and upper reference values) were extracted from our large healthy population. In fully adjusted models, advanced age was independently associated with cardiac structural remodeling and worsened diastolic parameters including larger indexed LA volume (LAVi), lower e', higher E/e', and higher TR velocity; all p<0.001), which were more prominent in women (P interaction: <0.05). Broadly, markedly lower e', higher E/e' and smaller LAVi were observed in ethnic Asians compared to Whites. DD defined by 2016 ASE criteria, despite at low prevalence (0.42%) in current healthy population, increased drastically with advanced age and performed perfectly in excluding abnormal NT-proBNP (≥125pg/mL) (Specificity: 99.8%, NPV: 97.6%). This is to date the largest cohort exploring the normative reference values using guideline-centered diastolic parameters from healthy Asians, with aging played as central role in diastolic dysfunction. Our observed sex and ethnic differences in defining healthy diastolic cut-offs likely impact future clinical definition for DD in Asians.

Abstract 15230: Sex and Racial Differences in Normative Reference Ranges and Healthy Aging on Diastolic Function in Ethnic Asians: 2016 Ase Guideline Revisited

Introduction: However, the reference ranges for echocardiography might be varying due to ethnicity, gender and age. Therefore, the normal reference ranges obtained from the healthy Asians are important for clinical utility of echocardiography in Asia. Methods: Population-based echocardiography dataset from 6,023 healthy ethnic Asians (47.1±10.9 years, 61.3% men) were divided into 6 age decades: ≤29, 30-39, 40-49, 50-59, 60-69 and ≥70 years. We explored age- and sex-related structural/functional alterations according to 2016 American Society of Echocardiography (ASE) diastolic dysfunction (DD) criteria and their correlates with clinical N-terminal pro-brain natriuretic peptide (NT-proBNP) cut-off for heart failure (HF). Racial comparisons were made using data from London Life Sciences Prospective Population (LOLIPOP) study. Results: Age- and sex-based normative reference ranges (including mean, median, 10% and 90% lower and upper reference values) were extracted from our large healthy population. In fully adjusted models, advanced age (treated as linear) was independently associated with cardiac structural remodeling and worsened diastolic parameters: larger indexed LA volume (LAVi), lower e’, higher E/e’, and higher TR velocity; all p &lt;0.001), and were broadly more prominent in women (P interaction : &lt;0.05). in general, markedly lower e’, higher E/e’ and smaller LAVi were observed in ethnic Asians compared to Whites. DD defined by 2016 ASE criteria, despite at low prevalence (0.42%) in current healthy population, increased drastically with advanced age and performed perfectly in excluding abnormal NT-proBNP (≥125 pg/ml) (Specificity: 99.8%, NPV: 97.6%). Conclusions: This is to date the largest cohort exploring the normative reference values using guideline-centered diastolic parameters from healthy Asians, with senescence process played as central role in diastolic dysfunction. Observed sex and ethnic differences in defining healthy diastolic cut-offs likely impact future clinical definition for DD.

Alcohol consumption is associated with widespread changes in blood DNA methylation: Analysis of cross-sectional and longitudinal data.

DNA methylation may be one of the mechanisms by which alcohol consumption is associated with the risk of disease. We conducted a large-scale, cross-sectional, genome-wide DNA methylation association study of alcohol consumption and a longitudinal analysis of repeated measurements taken several years apart. Using the Illumina HumanMethylation450 BeadChip, DNA methylation was measured in blood samples from 5606 Melbourne Collaborative Cohort Study (MCCS) participants. For 1088 of them, these measures were repeated using blood samples collected a median of 11 years later. Associations between alcohol intake and blood DNA methylation were assessed using linear mixed-effects regression models. Independent data from the London Life Sciences Prospective Population (LOLIPOP) (N = 4042) and Cooperative Health Research in the Augsburg Region (KORA) (N = 1662) cohorts were used to replicate associations discovered in the MCCS. Cross-sectional analyses identified 1414 CpGs associated with alcohol intake at P < 10-7 , 1243 of which had not been reported previously. Of these novel associations, 1078 were replicated (P < .05) using LOLIPOP and KORA data. Using the MCCS data, we also replicated 403 of 518 previously reported associations. Interaction analyses suggested that associations were stronger for women, non-smokers, and participants genetically predisposed to consume less alcohol. Of the 1414 CpGs, 530 were differentially methylated (P < .05) in former compared with current drinkers. Longitudinal associations between the change in alcohol intake and the change in methylation were observed for 513 of the 1414 cross-sectional associations. Our study indicates that alcohol intake is associated with widespread changes in DNA methylation across the genome. Longitudinal analyses showed that the methylation status of alcohol-associated CpGs may change with alcohol consumption changes in adulthood.

Training a model for estimating leukocyte composition using whole-blood DNA methylation and cell counts as reference.

Whole-blood DNA methylation depends on the underlying leukocyte composition and confounding hereby is a major concern in epigenome-wide association studies. Cell counts are often missing or may not be feasible. Computational approaches estimate leukocyte composition from DNA methylation based on reference datasets of purified leukocytes. We explored the possibility to train such a model on whole-blood DNA methylation and cell counts without the need for purification. Using whole-blood DNA methylation and corresponding five-part cell counts from 2445 participants from the London Life Sciences Prospective Population Study, a model was trained on a subset of 175 subjects and evaluated on the remaining. Correlations between cell counts and estimated cell proportions were high (neutrophils 0.85, eosinophils 0.88, basophils 0.02, lymphocytes 0.84, monocytes 0.55) and estimated proportions explained more variance in whole-blood DNA methylation levels than counts. Our model provided precise estimates for the common cell types.

Epigenome-wide association of DNA methylation markers in peripheral blood from Indian Asians and Europeans with incident type 2 diabetes: a nested case-control study

Indian Asians, who make up a quarter of the world's population, are at high risk of developing type 2 diabetes. We investigated whether DNA methylation is associated with future type 2 diabetes incidence in Indian Asians and whether differences in methylation patterns between Indian Asians and Europeans are associated with, and could be used to predict, differences in the magnitude of risk of developing type 2 diabetes. We did a nested case-control study of DNA methylation in Indian Asians and Europeans with incident type 2 diabetes who were identified from the 8-year follow-up of 25 372 participants in the London Life Sciences Prospective Population (LOLIPOP) study. Patients were recruited between May 1, 2002, and Sept 12, 2008. We did epigenome-wide association analysis using samples from Indian Asians with incident type 2 diabetes and age-matched and sex-matched Indian Asian controls, followed by replication testing of top-ranking signals in Europeans. For both discovery and replication, DNA methylation was measured in the baseline blood sample, which was collected before the onset of type 2 diabetes. Epigenome-wide significance was set at p<1 × 10(-7). We compared methylation levels between Indian Asian and European controls without type 2 diabetes at baseline to estimate the potential contribution of DNA methylation to increased risk of future type 2 diabetes incidence among Indian Asians. 1608 (11·9%) of 13 535 Indian Asians and 306 (4·3%) of 7066 Europeans developed type 2 diabetes over a mean of 8·5 years (SD 1·8) of follow-up. The age-adjusted and sex-adjusted incidence of type 2 diabetes was 3·1 times (95% CI 2·8-3·6; p<0·0001) higher among Indian Asians than among Europeans, and remained 2·5 times (2·1-2·9; p<0·0001) higher after adjustment for adiposity, physical activity, family history of type 2 diabetes, and baseline glycaemic measures. The mean absolute difference in methylation level between type 2 diabetes cases and controls ranged from 0·5% (SD 0·1) to 1·1% (0·2). Methylation markers at five loci were associated with future type 2 diabetes incidence; the relative risk per 1% increase in methylation was 1·09 (95% CI 1·07-1·11; p=1·3 × 10(-17)) for ABCG1, 0·94 (0·92-0·95; p=4·2 × 10(-11)) for PHOSPHO1, 0·94 (0·92-0·96; p=1·4 × 10(-9)) for SOCS3, 1·07 (1·04-1·09; p=2·1 × 10(-10)) for SREBF1, and 0·92 (0·90-0·94; p=1·2 × 10(-17)) for TXNIP. A methylation score combining results for the five loci was associated with future type 2 diabetes incidence (relative risk quartile 4 vs quartile 1 3·51, 95% CI 2·79-4·42; p=1·3 × 10(-26)), and was independent of established risk factors. Methylation score was higher among Indian Asians than Europeans (p=1 × 10(-34)). DNA methylation might provide new insights into the pathways underlying type 2 diabetes and offer new opportunities for risk stratification and prevention of type 2 diabetes among Indian Asians. The European Union, the UK National Institute for Health Research, the Wellcome Trust, the UK Medical Research Council, Action on Hearing Loss, the UK Biotechnology and Biological Sciences Research Council, the Oak Foundation, the Economic and Social Research Council, Helmholtz Zentrum Munchen, the German Research Center for Environmental Health, the German Federal Ministry of Education and Research, the German Center for Diabetes Research, the Munich Center for Health Sciences, the Ministry of Science and Research of the State of North Rhine-Westphalia, and the German Federal Ministry of Health.

A low-frequency variant in MAPK14 provides mechanistic evidence of a link with myeloperoxidase: a prognostic cardiovascular risk marker.

BackgroundGenetics can be used to predict drug effects and generate hypotheses around alternative indications. To support Losmapimod, a p38 mitogen‐activated protein kinase inhibitor in development for acute coronary syndrome, we characterized gene variation in MAPK11/14 genes by exome sequencing and follow‐up genotyping or imputation in participants well‐phenotyped for cardiovascular and metabolic traits.Methods and ResultsInvestigation of genetic variation in MAPK11 and MAPK14 genes using additive genetic models in linear or logistic regression with cardiovascular, metabolic, and biomarker phenotypes highlighted an association of RS2859144 in MAPK14 with myeloperoxidase in a dyslipidemic population (Genetic Epidemiology of Metabolic Syndrome Study), P=2.3×10−6). This variant (or proxy) was consistently associated with myeloperoxidase in the Framingham Heart Study and Cardiovascular Health Study studies (replication meta‐P=0.003), leading to a meta‐P value of 9.96×10−7 in the 3 dyslipidemic groups. The variant or its proxy was then profiled in additional population‐based cohorts (up to a total of 58 930 subjects) including Cohorte Lausannoise, Ely, Fenland, European Prospective Investigation of Cancer, London Life Sciences Prospective Population Study, and the Genetics of Obesity Associations study obesity case–control for up to 40 cardiovascular and metabolic traits. Overall analysis identified the same single nucleotide polymorphisms to be nominally associated consistently with glomerular filtration rate (P=0.002) and risk of obesity (body mass index ≥30 kg/m2, P=0.004).ConclusionsAs myeloperoxidase is a prognostic marker of coronary events, the MAPK14 variant may provide a mechanistic link between p38 map kinase and these events, providing information consistent with current indication of Losmapimod for acute coronary syndrome. If replicated, the association with glomerular filtration rate, along with previous biological findings, also provides support for kidney diseases as alternative indications.

Population-Based Reference Values for 3D Echocardiographic LV Volumes and Ejection Fraction

The purpose of this study was to define age-, sex-, and ethnicity-specific reference values for 3-dimensional echocardiographic (3DE) left ventricular (LV) volumes and LV ejection fraction (LVEF) in a large cohort of European white and Indian Asian subjects. Transthoracic 3DE imaging is recommended for the routine evaluation of LV volumes and function. However, there remains a lack of population-based reference values for 3DE LV volumes and LVEF, hindering adoption of this technique into routine clinical practice. We identified subjects from the LOLIPOP (London Life Sciences Prospective Population) study who were free of clinical cardiovascular disease, hypertension, and type 2 diabetes. All subjects underwent transthoracic 2-dimensional and 3D echocardiography for quantification of LV end-systolic volume index, LV end-diastolic volume index, and LVEF. 3DE image quality was satisfactory in 978 subjects (89%) for the purposes of LV volumetric analysis. Indexed 3DE LV volumes were significantly smaller in female compared with male subjects and in Indian Asians compared with European whites. Upper limit of normal (mean ± 2 SD) reference values for the LV end-systolic volume index and LV end-diastolic volume index for the 4 ethnicity-sex subgroups were, respectively, as follows: European white men, 29 ml/m(2) and 67 ml/m(2); Indian Asian men, 26 ml/m(2) and 59 ml/m(2); European white women, 24 ml/m(2) and 58 ml/m(2); Indian Asian women, 23 ml/m(2) and 55 ml/m(2), respectively. Compared with 3DE studies, 2-dimensional echocardiography underestimated the LV end-systolic volume index and LV end-diastolic volume index by an average of 2.0 ml/m(2) and 4.7 ml/m(2), respectively. LVEF was similar between in all 4 groups and between 2- and 3-dimensional techniques, with a lower cutoff of 52% for the whole cohort. These reference values are based on the largest 3DE study performed to date that should facilitate the standardization of the technique and encourage its adoption for the routine assessment of LV volumes and LVEF in the clinical echocardiography laboratory. This study supports the application of ethnicity-specific reference values for indexed LV volumes.

The increased prevalence of left ventricular hypertrophy and concentric remodeling in UK Indian Asians compared with European Whites

Individuals of Indian Asian ethnicity living in the U.K. have at least a 50% excess of cardiovascular disease (CVD) mortality compared with European whites, yet there are no validated tools capable of identifying this excess risk. Left ventricular hypertrophy (LVH) is a powerful prognosticator for future CVD events but its prevalence in Indian Asians is unknown. We examined the prevalence of LVH and the degree of concentric remodeling amongst healthy U.K. Indian Asians compared with European whites recruited to the LOLIPOP (London Life Sciences Prospective Population) study. Transthoracic echocardiography was performed in 2127 subjects aged 35-75 years without history of clinical CVD events. The prevalence of LVH was defined and relative wall thickness was calculated to provide a measure of concentric remodeling. The prevalence of LVH was significantly higher amongst Indian Asian men as compared with European white men, with an unadjusted odds ratio (OR) of 1.8 (95% CI: 1.4-2.6). Following adjustment for clinical and hemodynamic variables, the magnitude of this effect increased (OR 2.8, 95% CI: 1.9-4.2). The degree of concentric remodeling was higher amongst Indian Asians as compared with European whites (adjusted relative wall thickness for men: 0.41 vs. 0.39, P<0.001; women: 0.40 vs. 0.38, P<0.01). An almost threefold higher prevalence of LVH amongst Indian Asian men and a greater degree of concentric remodeling amongst Indian Asian men and women was evident. Investigation of the mechanisms underlying the pathogenesis of LV remodeling and blood pressure etiology may help redress the excess CVD mortality observed in Indian Asians.

Fine-scale estimation of location of birth from genome-wide single-nucleotide polymorphism data.

Systematic nonrandom mating in populations results in genetic stratification and is predominantly caused by geographic separation, providing the opportunity to infer individuals' birthplace from genetic data. Such inference has been demonstrated for individuals' country of birth, but here we use data from the Northern Finland Birth Cohort 1966 (NFBC1966) to investigate the characteristics of genetic structure within a population and subsequently develop a method for inferring location to a finer scale. Principal component analysis (PCA) shows that while the first PCs are particularly informative for location, there is also location information in the higher-order PCs, but it cannot be captured by a linear model. We introduce a new method, pcLOCATE, which is able to exploit this information to improve the accuracy of location inference. pcLOCATE uses individuals' PC values to estimate the probability of birth in each town and then averages over all towns to give an estimated longitude and latitude of birth using a fully Bayesian model. We apply pcLOCATE to the NFBC1966 data to estimate parental birthplace, testing with successively more PCs and finding the model with the top 23 PCs most accurate, with a median distance of 23 km between the estimated and the true location. pcLOCATE predicts the most recent residence of NFBC1966 individuals to a median distance of 47 km. We also apply pcLOCATE to Indian individuals from the London Life Sciences Prospective Population Study (LOLIPOP) data, and find that birthplace is predicated to a median distance of 54 km from the true location. A method with such accuracy is potentially valuable in population genetics and forensics.

P07 Socio-demographic and behavioural determinants of abnormal liver function in a multi ethnic population in the UK: the LOLIPOP study

IntroductionFatty liver disease (FLD) is common, with an estimated prevalence between 10 and 24% of the general population. Most patients are asymptomatic, and identified via incidental abnormal liver function tests,...

Does subclinical atherosclerosis burden identify the increased risk of cardiovascular disease mortality among United Kingdom Indian Asians? A population study

Indian Asians living in the United Kingdom have a >50% higher risk of cardiovascular disease (CVD) death compared with native European whites. The mechanisms underlying their excess mortality are not clear, and there are no validated tools capable of identifying this increased risk. The burden of subclinical atherosclerosis detected in the carotid arteries is an established prognosticator for major CVD events. We hypothesized that the increased prevalence of CVD among Indian Asians would be reflected by their having a greater burden of subclinical carotid artery atherosclerosis compared with European whites. We studied 2,288 healthy subjects and 148 patients with known CVD from the London Life Sciences Prospective Population study who underwent carotid ultrasonography for assessment of intima-media thickness (IMT), plaque prevalence, and plaque echogenicity. The prevalence of CVD was significantly higher among Indian Asians compared with European whites (odds ratio 1.72, 95% CI 1.2-2.3). Intima-media thickness was slightly higher in European whites compared with that of Indian Asians (0.66 vs 0.65 mm, P = .06), reflecting their higher Framingham Risk Score. After adjustment for cardiovascular risk factors, there were no significant differences in IMT, plaque prevalence, or plaque echogenicity between the 2 ethnic groups regardless of CVD status. The burden of carotid atherosclerosis does not identify the markedly increased risk of CVD among United Kingdom Indian Asians. Other markers and mechanisms of disease require investigation in this high-risk group.

The CXCL16 A181V Mutation Selectively Inhibits Monocyte Adhesion to CXCR6 but Is Not Associated With Human Coronary Heart Disease

The chemokine CXCL16 serves as a scavenger receptor for oxidized low-density lipoprotein and as an adhesion molecule and chemoattractant for cells expressing the receptor CXCR6. A commonly occurring CXCL16 allele has been described containing 2 nonsynonymous single-nucleotide polymorphisms in complete linkage disequilibrium, although the effects on CXCL16 function are unknown. Here, we examined the effect of the single-nucleotide polymorphisms on CXCL16 function and assessed the association of the mutant allele with coronary heart disease (CHD). Both wild-type and mutant T123V181-CXCL16 were readily expressed in vitro and were similarly functional in assays of oxidized low-density lipoprotein scavenging and chemotaxis. However, unlike wild-type CXCL16, T123V181-CXCL16 was unable to promote adhesion of CXCR6(+) cells. Findings were confirmed ex vivo, with monocytes from donors homozygous for the T123V181 allele unable to facilitate adhesion of CXCR6 transfectants. In the London Life Sciences Prospective Population cohort (n = 2797), we found that the T123V181 allele was not associated with protection or susceptibility to CHD (adjusted odds ratio, 1.01; 95% CI, 0.95 to 1.10; P = 0.74). CXCL16-mediated cell adhesion plays at best a modest role in CHD, and the scavenging and chemotactic properties of the chemokine are more likely to be more important in disease pathogenesis.

The Distinct Relationships of Carotid Plaque Disease and Carotid Intima-Media Thickness with Left Ventricular Function

Subclinical carotid atherosclerosis has been associated with impaired left ventricular (LV) function and the development of heart failure. Whether impaired LV function is related primarily to increased intima-media thickness (IMT) or burden of plaque disease or both remains to be determined. A total of 2,279 subjects without clinical cardiovascular disease recruited from the London Life Sciences Prospective Population cohort study were studied. Carotid ultrasonography and transthoracic echocardiography were performed on all subjects. Carotid IMT and plaque scores were measured, and their relationships with LV volumes, LV ejection fraction, myocardial LV longitudinal function (Sa and Ea velocities), and LV filling pressure (E/Ea ratio) were assessed before and after adjustment for covariates. Compared with those without carotid artery disease, subjects with either increased IMT and/or presence of plaque disease had identical Sa velocities (both 9.0 cm/sec), lower Ea velocities (8.7 vs 9.9 cm/sec, P < .001) and higher E/Ea ratios (8.4 vs 7.6, P < .001). After multiple linear regression analysis, increasing IMT remained independently related to reduced Ea velocity (P < .001) but not LV ejection fraction, Sa velocity, or E/Ea ratio. In a separate adjusted analysis, subjects with severe burdens of carotid plaque disease (more than five plaques) had reduced LV ejection fractions (β = -2.9; 95% confidence interval [CI], 1.0 to 4.8, P = .003), attenuated Sa velocities (β = -0.79; 95% CI, -1.2 to -0.3, P = .003), attenuated Ea velocities 2 (β = -0.79; 95% CI, -1.3 to -0.2, P = .007), and increased E/Ea ratios (β = 0.84; 95% CI, 0.2 to 1.5, P = .009) compared to individuals without carotid plaques. These findings demonstrate that subclinical carotid plaque disease rather than IMT is more closely related to LV systolic function and LV filling pressure. These data support the application of carotid ultrasonography beyond cardiovascular disease risk prediction, while providing insight into potential mechanisms underlying the development of subclinical LV dysfunction.

111 Increased carotid artery plaque burden is associated with reduced systolic left ventricular function and increased filling pressure in asymptomatic individuals

Introduction Increased carotid intima-media thickness (IMT) and the presence of carotid plaques are both considered surrogate markers of atherosclerosis. Although inter-related, these two phenotypes represent heterogenous pathophysiological processes. Increased IMT is largely correlated to normal ageing and blood pressure, whereas plaques are synonymous with established atherosclerosis. We sought to determine the distinct relationships of carotid intima-media thickness and carotid plaque disease with quantitative parameters of left ventricular (LV) function. Methods We studied 2279 healthy subjects recruited from the LOLIPOP (London Life Sciences Prospective Population) study free of clinical cardiovascular disease. Bilateral carotid ultrasonography was performed on all subjects to determine presence of carotid plaque, with the total number of plaques identified providing a plaque score. Subjects with a plaque score of 0, 1–2, 3–5 and > 5 were classified as having no, mild, moderate and severe plaque burden respectively. Tissue Doppler imaging was performed on all subjects for derivation of parameters of LV longitudinal function and filling pressure (myocardial Sa velocity, myocardial Ea velocity and the E/Ea ratio). Results Subjects with higher plaque score were older, more likely to be male, have a greater prevalence of hypertension, diabetes and history of cigarette smoking (all p Conclusions This study confirms that distinct relationships exist between different forms of carotid artery disease and LV function. Carotid plaque disease severity, but not increased IMT, is associated with reduced systolic function and increased LV filling pressure in asymptomatic individuals.

New insights into the relationship of left ventricular geometry and left ventricular mass with cardiac function: a population study of hypertensive subjects

Remodelling of the left ventricle (LV) is associated with adverse cardiovascular events, but the mechanisms of these effects remain undefined. We investigated the relationship of LV mass and geometry to LV function in a large cohort of hypertensive subjects. We studied 1074 hypertensive individuals without cardiovascular disease recruited from the London Life Sciences Prospective Population (LOLIPOP) study. All subjects underwent echocardiography for derivation of LV mass index (LVMI), measurement of transmitral filling pattern, and LV ejection fraction (EF). The tissue Doppler parameters of peak myocardial systolic velocity (Sa), diastolic velocity (Ea), and of LV filling pressure (E/Ea) were measured. Left ventricular function was correlated with degree of concentric remodelling, determined by relative wall thickness, and with LV geometric pattern. The presence of LV hypertrophy was independently associated with significantly worse systolic function, diastolic function, and higher LV filling pressure when compared with subjects with normal LV geometry or non-hypertrophic concentric remodelling. After adjustment for covariates including LVMI, peak Sa velocity and EF increased (P < 0.001), whereas peak Ea velocity decreased significantly (P < 0.001) with increasing degrees of concentric remodelling. In hypertensives, hypertrophic remodelling is independently associated with impaired LV function and increased LV filling pressure. Increasing degrees of non-hypertrophic concentric remodelling are associated with attenuated diastolic function, but augmented systolic function, possibly representing an adaptive response to pressure overload physiology.

Normative reference values for the tissue Doppler imaging parameters of left ventricular function: a population-based study

Tissue Doppler imaging (TDI) is used routinely to quantify left ventricular function and filling pressure. However, there remains a lack of percentile-based normative reference values for these clinically important parameters. Four hundred and fifty-three healthy subjects aged 35-75 years were included for analysis from the London Life Sciences Prospective Population (LOLIPOP) study. Subjects were free of manifest cardiovascular disease, cardiovascular risk factors, and significant coronary artery disease as determined by electron-beam computed tomography. They underwent 2D and Doppler echocardiography for assessment of left heart structure and function. TDI was performed at the septal and lateral mitral annular sites enabling on-line derivation of myocardial systolic velocity (Sa), diastolic velocity (Ea), and the ratio of Ea to transmitral E-wave (E/Ea). Reference ranges (5th and 95th percentile values) for septal, lateral, and average mitral annular Sa velocity, Ea velocity, and E/Ea ratio were derived for the whole cohort and for each of the four age groups (35-44, 45-54, 55-64, 65-75). Increasing age was associated with a significant attenuation in myocardial velocity when averaged from both the septal and lateral mitral annulus, exerting a greater influence upon average Ea velocity (P < 0.001) compared with average Sa velocity (P = 0.04). Average E/Ea ratio increased significantly with advancing age (P < 0.001). The reference ranges presented for the TDI parameters of Sa velocity, Ea velocity, and E/Ea ratio will help to standardize the assessment of LV function by tissue Doppler echocardiography.

Ethnicity-related differences in left ventricular function, structure and geometry: a population study of UK Indian Asian and European white subjects

ObjectivesThe authors studied healthy UK Indian Asian and European white subjects to assess whether functional, structural and geometrical properties of the left heart are intrinsically related to ethnicity.BackgroundQuantitative assessment of...

Abstract 3227: Contribution Of Known Genetic Factors To Increased Risk Of Type-2 Diabetes In Indian Asians

Background. Type-2 diabetes (T2D) is 2– 4 fold more common amongst Indian Asians than North American and European whites, and is a major contributor to two-fold higher cardiovascular disease mortality in Asians. We investigated whether genetic variation in the validated T2D genes, contributes to the increased risk of T2D amongst Indian Asians, compared to European whites. Methods. We examined the association of genetic variants in the 16 validated T2D genes with T2D amongst 9,776 Indian Asian and 4,407 European white men and women, aged 35–75 years, participating in the London Life Sciences Prospective Population (LOLIPOP) study. Genotyping was performed by competitive allele-specific PCR (KASPar). Results. Indian Asians had higher T2D prevalence (20.9% vs 8.7%, P&lt;0.001), despite lower age (50.3±10.9 vs 52.1±11.6, P&lt;0.001) and body mass index (26.9±4.1 vs 27.6±4.7, P&lt;0.001), compared to Europeans. Genotyping confirmed association of WFS1, SLC30A8, PPARG, IGF2BP2, TCF7L2, JAZF1, CDKN2A/B, HHEX/IDE and FTO with T2D in both populations (P&lt;0.05). Associations of CDKAL1 , KCNJ11, THADA, CDC123-CAMK1D, ADAMTS9, TSPAN8-LGR5 or NOTCH2 with T2D did not reach statistical significance. SNP risk allele frequency was higher for six, but lower for nine, in Indian Asians compared to Europeans. In regression analysis, risk of T2D remained 3.6 (95%CI 3.2– 4.1, P&lt;0.001) fold higher amongst Indian Asians compared to Europeans, despite adjustment for age, body mass index and known genetic factors. Discussion. Known genetic variants show similar association with T2D, and have similar risk allele frequencies, amongst Indian Asians and Europeans. These genetic factors do not account for the three-fold increased risk of T2D amongst Indian Asians.