[Show abstract][Hide abstract] ABSTRACT: The impact of fast changes in obesity indices on other measures of metabolic health is poorly defined in the general population. Using the Polish accession to the European Union as a model of political and social transformation we examined how an expected rapid increase in body mass index (BMI) and waist circumference relates to changes in lipid profile, both at the population and personal level.
Through primary care centres in 444 Polish cities, two cross-sectional nationwide population-based surveys (LIPIDOGRAM 2004 and LIPIDOGRAM 2006) examined 15,404 and 15,453 adult individuals in 2004 and 2006, respectively. A separate prospective sample of 1,840 individuals recruited in 2004 had a follow-up in 2006 (LIPIDOGRAM PLUS).
Two years after Polish accession to European Union, mean population BMI and waist circumference increased by 0.6% and 0.9%, respectively. This tracked with a 7.6% drop in HDL-cholesterol and a 2.1% increase in triglycerides (all p<0.001) nationwide. The direction and magnitude of the population changes were replicated at the personal level in LIPIDOGRAM PLUS (0.7%, 0.3%, 8.6% and 1.8%, respectively). However, increases in BMI and waist circumference were both only weakly associated with HDL-cholesterol and triglycerides changes prospectively. The relation of BMI to the magnitude of change in both lipid fractions was comparable to that of waist circumference.
Moderate changes in obesity measures tracked with a significant deterioration in measures of pro-atherogenic dyslipidaemia at both personal and population level. These associations were predominantly driven by factors not measureable directly through either BMI or waist circumference.
PLoS ONE 01/2014; 9(1):e86837. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To derive cut-points for body mass index (BMI) and waist circumference (WC) for minority ethnic groups that are risk equivalent based on endogenous glucose levels to cut-points for white Europeans (BMI 30 kg/m2; WC men 102 cm; WC women 88 cm).
Cross-sectional data from participants aged 40-75 years: 4,672 white and 1,348 migrant South Asian participants from ADDITION-Leicester (UK) and 985 indigenous South Asians from Jaipur Heart Watch/New Delhi studies (India). Cut-points were derived using fractional polynomial models with fasting and 2-hour glucose as outcomes, and ethnicity, objectively-measured BMI/WC, their interaction and age as covariates.
Based on fasting glucose, obesity cut-points were 25 kg/m2 (95% Confidence Interval: 24, 26) for migrant South Asian, and 18 kg/m2 (16, 20) for indigenous South Asian populations. For men, WC cut-points were 90 cm (85, 95) for migrant South Asian, and 87 cm (82, 91) for indigenous South Asian populations. For women, WC cut-points were 77 cm (71, 82) for migrant South Asian, and 54 cm (20, 63) for indigenous South Asian populations. Cut-points based on 2-hour glucose were lower than these.
These findings strengthen evidence that health interventions are required at a lower BMI and WC for South Asian individuals. Based on our data and the existing literature, we suggest an obesity threshold of 25 kg/m2 for South Asian individuals, and a very high WC threshold of 90 cm for South Asian men and 77 cm for South Asian women. Further work is required to determine whether lower cut-points are required for indigenous, than migrant, South Asians.
PLoS ONE 01/2014; 9(3):e90813. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The interleukin-6 receptor (IL-6R) blocker tocilizumab (TCZ) reduces inflammatory disease activity in rheumatoid arthritis (RA) but elevates lipid concentrations in some patients. We aimed to characterise the impact of IL-6R inhibition on established and novel risk factors in active RA.
Randomised, multicentre, two-part, phase III trial (24-week double-blind, 80-week open-label), MEASURE, evaluated lipid and lipoprotein levels, high-density lipoprotein (HDL) particle composition, markers of coagulation, thrombosis and vascular function by pulse wave velocity (PWV) in 132 patients with RA who received TCZ or placebo.
Median total-cholesterol, low-density lipoprotein-cholesterol (LDL-C) and triglyceride levels increased in TCZ versus placebo recipients by week 12 (12.6% vs 1.7%, 28.1% vs 2.2%, 10.6% vs -1.9%, respectively; all p<0.01). There were no significant differences in mean small LDL, mean oxidised LDL or total HDL-C concentrations. However, HDL-associated serum amyloid A content decreased in TCZ recipients. TCZ also induced reductions (>30%) in secretory phospholipase A2-IIA, lipoprotein(a), fibrinogen and D-dimers and elevation of paraoxonase (all p<0.0001 vs placebo). The ApoB/ApoA1 ratio remained stable over time in both groups. PWV decreases were greater with placebo than TCZ at 12 weeks (adjusted mean difference 0.79 m/s (95% CI 0.22 to 1.35; p=0.0067)).
These data provide the first detailed evidence for the modulation of lipoprotein particles and other surrogates of vascular risk with IL-6R inhibition. When compared with placebo, TCZ induced elevations in LDL-C but altered HDL particles towards an anti-inflammatory composition and favourably modified most, but not all, measured vascular risk surrogates. The net effect of such changes for cardiovascular risk requires determination.
Annals of the rheumatic diseases 12/2013; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background and Aims: Previous studies have investigated the association between ethnicity and processes of care and intermediate outcomes of diabetes, but there are limited population-based studies available. The aim of this study was to use population-based data to investigate the relationships between ethnicity and glycaemic control in men and women with diabetes mellitus living in Scotland Methods: We used a 2008 extract from the population-based national electronic diabetes database of Scotland. The association between ethnicity with mean glycaemic control in type 2 diabetes mellitus was examined in a retrospective cohort study, including adjustment for a number of variables including age, sex, socioeconomic status, body mass index (BMI), prescribed treatment and duration of diabetes. Results: Complete data for analyses were available for 56,333 White Scottish adults, 2,535 Pakistanis, 857 Indians, 427 Chinese and 223 African-Caribbeans. All other ethnic groups had significantly (p,0.05) greater proportions of people with suboptimal glycaemic control (HbA1c .58 mmol/mol, 7.5%) compared to the White Scottish group, despite generally younger mean age and lower BMI. Fully adjusted odds ratios for suboptimal glycaemic control were significantly higher among Pakistanis and Indians (1.85, 95% CI: 1.68–2.04, and 1.62,95% CI: 1.38–1.89) respectively. Conclusions: Pakistanis and Indians with type 2 diabetes mellitus were more likely to have suboptimal glycaemic control than the white Scottish population. Further research on health services and self-management are needed to understand the association between ethnicity and glycaemic control to address ethnic disparities in glycaemic control. Copyright: ß 2013 Negandhi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The authors have no support or funding to report. Competing Interests: HMC received monies from Pfizer for attending symposia, a speaker's bureau, as a member of staff and for consultancy. HMC has received research funds from Pfizer, Roche, Eli-Lilly, Boehringer Ingelheim (BI) and Astra Zeneca. HMC has shares in Roche. JAM is the PI for drug studies for Novo Nordisk, Eli Lilly and BI (contracts relating to this work are through JAM's NHS employer R&D department). JAM received monies 2 years ago from BI for organising the ethics application for their study and attending the meeting relating to this. JAM has received support to attend meetings from the above companies as well as from Takeda. This does not alter the authors' adherence to all PLOS ONE policies on sharing materials.
[Show abstract][Hide abstract] ABSTRACT: We investigated 3 hypotheses: (1) N-terminal pro-B-type natriuretic peptide (NT-proBNP) predicts cardiovascular disease events in patients with hypertension, (2) NT-proBNP is associated with blood pressure variability, and (3) NT-proBNP predicts benefit from antihypertensive regimens. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) randomized a subset of 6549 patients at risk with no history of coronary heart disease to either atenolol-based or amlodipine-based blood pressure-lowering treatment. During 5.5 years of follow-up, 485 cardiovascular disease cases accrued and were matched with 1367 controls. Baseline and 6-month in-trial NT-proBNP were measured. The results show that NT-proBNP improves cardiovascular disease risk prediction beyond established predictors, continuous net reclassification improvement of 22.3% (P<0.0001). Furthermore, a 1-mm Hg increase in the SD of systolic blood pressure was associated with 2% higher baseline NT-proBNP in a multivariable regression analysis (P<0.0001). However, NT-proBNP predicted cardiovascular disease risk independently of blood pressure variation (odds ratio per SD increase in log NT-proBNP 1.24; 95% confidence interval, 1.06-1.45; P=0.007). Atenolol-based treatment led to a 69.6% increase in NT-proBNP at 6 months (P<0.0001). In contrast, amlodipine-based treatment reduced NT-proBNP by 36.5% (P<0.0001). Amlodipine recipients who achieved a 6-month NT-proBNP below the median (61 pg/mL) were at lower risk of cardiovascular disease when compared with those who did not (odds ratio, 0.58; 95% confidence interval, 0.37-0.91) after adjustment for confounders inclusive of baseline NT-proBNP and achieved blood pressure. If confirmed, these novel results suggest that NT-proBNP, as well as aiding cardiovascular disease risk assessment, may also help assess the efficacy of specific antihypertensive regimens. Further relevant studies seem warranted.
[Show abstract][Hide abstract] ABSTRACT: There is evidence that South Asian individuals have higher fat mass for a given weight than Europeans. One study reported that the greater fatness for a given birthweight may increase with increasing birthweight, suggesting that any attempt to increase mean birthweight in South Asians would markedly increase their fatness.
Our objective was to examine whether differences in cord leptin values between White British and Pakistani infants vary by birthweight category.Method We examined the difference in cord leptin levels between 659 White British and 823 Pakistani infants recruited to the Born in Bradford cohort study, by clinical categories and thirds of the birthweight distribution.
Pakistani infants had a lower mean birthweight but higher cord leptin levels than White British infants [ratio of geometric mean (RGM) of cord leptin adjusted for birthweight = 1.36 (95% CI 1.26, 1.46)]. Birthweight was positively associated with cord leptin levels in both groups, with no evidence that the regression lines in the two groups diverged from each other with increasing birthweight. The relative ethnic difference in cord leptin was similar in low (<2500 g), normal and high (≥4000 g) birthweight infants (P-value for interaction = 0.91). It was also similar across thirds of the birthweight distribution [RGM (95% CI) in lowest, mid and highest thirds were 1.37 (1.20, 1.57), 1.36 (1.20, 1.54) and 1.31 (1.16, 1.52), respectively, P-interaction = 0.51].
We found marked differences in cord leptin levels between Pakistani and White British infants but no evidence that this difference increases with increasing birthweight.
International Journal of Epidemiology 11/2013; · 6.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We have investigated the role of muscle mass, natriuretic peptides and adipokines in explaining the obesity paradox.
The obesity paradox relates to the association between obesity and increased survival in patients with coronary heart disease (CHD) or heart failure (HF).
Prospective study of 4046 men aged 60-79years followed up for a mean period of 11years, during which 1340 deaths occurred. The men were divided according to the presence of doctor diagnosed CHD and HF: (i) no CHD or HF ii), with CHD (no HF) and (iii) with HF.
Overweight (BMI 25-9.9kg/m(2)) and obesity (BMI≥30kg/m(2)) were associated with lower mortality risk compared to men with normal weight (BMI 18.5-24.9kg/m(2)) in those with CHD [hazards ratio (HR) 0.71 (0.56,0.91) and 0.77 (0.57,1.04); p=0.04 for trend] and in those with HF [HR 0.57 (0.28,1.16) and 0.41 (0.16,1.09; p=0.04 for trend). Adjustment for muscle mass and NT-proBNP attenuated the inverse association in those with CHD (no HF) [HR 0.78 (0.61,1.01) and 0.96 (0.68,1.36) p=0.60 for trend) but made minor differences to those with HF [p=0.05]. Leptin related positively to mortality in men without HF but inversely to mortality in those with HF; adjustment for leptin abolished the BMI mortality association in men with HF [HR 0.82 (0.31,2.20) and 0.99 (0.27,3.71); p=0.98 for trend].
The lower mortality risk associated with excess weight in men with CHD without HF may be due to higher muscle mass. In men with HF, leptin (possibly reflecting cachexia) explain the inverse association.
International journal of cardiology 11/2013; · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treat-to-target strategies have been widely adopted as the standard of care for the management of patients with rheumatoid arthritis. The concept of 'tight control' is prevalent in other disciplines, particularly in diabetes and cardiovascular risk management. In these disciplines, evidence has accumulated that the utility of tight control strategies must be carefully weighed against the disutility that may arise from multiple interventions, particularly in patients at low risk. There is a lively debate in rheumatology circles about whether treatment should be targeted at achieving low disease activity, clinical remission or imaging remission. As rheumatologists we should learn the lessons from other disciplines, and ensure that we expand the evidence base to ensure our recommendations are securely underpinned by robust evidence.
Annals of the rheumatic diseases 11/2013; · 8.11 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective
Diabetes is associated with left ventricular diastolic and systolic dysfunction. South Asians may be at particular risk of developing LV dysfunction due to a high prevalence of diabetes. We investigated the role of diabetes and hyperglycaemia in LV dysfunction in a community-based cohort of older South Asians and White Europeans.Research Design and Methods
Conventional and Doppler echocardiography was performed in 999 participants (542 Europeans, 457 South Asians aged 58-86 years) in a population-based study. Anthropometry, fasting bloods, coronary artery calcification scoring, blood pressure and renal function were measured.ResultsDiabetes, and hyperglycaemia across the spectrum of HbA1c had a greater adverse effect on LV function in South Asians than Europeans (NT-proBNP beta±SE 0.09±0.04, p=0.01 versus -0.04±0.05, p=0.4, p for HbA1c/ethnicity interaction 0.02), diastolic function (E/e' 0.69±0.12, p<0.0001 versus 0.09±0.2, p=0.6, p interaction 0.005, and systolic function (s' -0.11±0.06, p=0.04 versus 0.14±0.09, p=0.1, p interaction 0.2). Multivariable adjustment for hypertension, microvascular disease, LV mass, coronary disease and dyslipidaemia only partially accounted for the ethnic differences. Adverse LV function in diabetic South Asians could not be accounted for by poorer glycaemic control or longer diabetes duration.Conclusions
Diabetes and hyperglycaemia have a greater adverse effect on LV function in South Asians than Europeans incompletely explained by adverse risk factors. South Asians may require earlier, and more aggressive treatment of their cardiometabolic risk factors to reduce risks of LV dysfunction.
[Show abstract][Hide abstract] ABSTRACT: To evaluate QRISK2 and Framingham cardiovascular disease (CVD) risk scores in a tri-ethnic UK population.
Randomly selected from primary care lists. Follow-up data were available for 87% of traced participants, comprising 1866 white Europeans, 1377 South Asians, and 578 African Caribbeans, aged 40-69 years at baseline (1998-1991).
First CVD events: myocardial infarction, coronary revascularisation, angina, transient ischaemic attack or stroke reported by participant, primary care or hospital records or death certificate.
During follow-up, 387 CVD events occurred in men (14%) and 78 in women (8%). Both scores underestimated risk in European and South Asian women (ratio of predicted to observed risk: European women: QRISK2: 0.73, Framingham: 0.73; South Asian women: QRISK2: 0.52, Framingham: 0.43). In African Caribbeans, Framingham over-predicted in men and women and QRISK2 over-predicted in women. Framingham classified 28% of participants as high risk, predicting 54% of all such events. QRISK2 classified 19% as high risk, predicting 42% of all such events. Both scores performed poorly in identifying high risk African Caribbeans; QRISK2 and Framingham identified as high risk only 10% and 24% of those who experienced events.
Neither score performed consistently well in all ethnic groups. Further validation of QRISK2 in other multi-ethnic datasets, and better methods for identifying high risk African Caribbeans and South Asian women, are required.
[Show abstract][Hide abstract] ABSTRACT: To examine the association of total cerebral blood flow (CBF) with all-cause, noncardiovascular, and cardiovascular mortality in older subjects at risk of cardiovascular disease.
We included 411 subjects with a mean age of 74.5 years from the MRI substudy of the Prospective Study of Pravastatin in the Elderly at Risk. Total CBF was measured at baseline, and occurrence of death was recorded in an average follow-up period of 11.8 years. For each participant, total CBF was standardized for brain parenchymal volume. Cox regression models were used to estimate risk of all-cause, noncardiovascular, and cardiovascular mortality in relation to CBF.
Mortality rates among participants in low, middle, and high thirds of total CBF were 52.1, 41.5, and 28.7 per 1,000 person-years, respectively. Compared with participants in the high third of CBF, participants in the low third had 1.88-fold (95% confidence interval [CI]: 1.30-2.72) higher risk of all-cause mortality, 1.66-fold (95% CI: 1.06-2.59) higher risk of noncardiovascular mortality, and 2.50-fold (95% CI: 1.28-4.91) higher risk of cardiovascular mortality. Likewise, compared with participants in the high third of CBF, participants in the middle third had 1.44-fold (95% CI: 0.98-2.11) higher risk of all-cause mortality, 1.29-fold (95% CI: 0.82-2.04) higher risk of noncardiovascular mortality, and 1.86-fold (95% CI: 0.93-3.74) higher risk of cardiovascular mortality. These associations were independent of prevalent vascular status and risk factors.
Low total CBF is linked with higher risk of all-cause, noncardiovascular, and cardiovascular mortality in older people independent of clinical cardiovascular status.
[Show abstract][Hide abstract] ABSTRACT: Lower maternal vitamin D status in pregnancy may be associated with increased offspring cardiovascular risk in later life, but evidence for this is scant. We examined associations of maternal total 25-hydroxyvitamin D (25(OH)D) in pregnancy with offspring cardiovascular risk factors assessed in childhood and adolescence.
A longitudinal, prospective study.
The study was based on data from mother-offspring pairs in the Avon Longitudinal Study of Parents and Children (ALSPAC), a UK prospective population-based birth cohort (N=4109).
Offspring cardiovascular risk factors were measured in childhood (mean age 9.9 years) and in adolescence (mean age 15.4 years): blood pressure, lipids, apolipoproteins (at 9.9 years only), glucose and insulin (at 15.4 years only), C reactive protein (CRP), and interleukin 6 (at 9.9 years only) were measured.
After adjustments for potential confounders (maternal age, education, body mass index (BMI), smoking, physical activity, parity, socioeconomic position, ethnicity, and offspring gestational age at 25(OH)D sampling; gender, age, and BMI at outcome assessment), maternal 25(OH)D was inversely associated with systolic blood pressure (-0.48 mm Hg difference per 50 nmol/L increase in 25(OH)D; 95% CI -0.95 to -0.01), Apo-B (-0.01 mg/dL difference; 95% CI -0.02 to -0.001), and CRP (-6.1% difference; 95% CI -11.5% to -0.3%) at age 9.9 years. These associations were not present for risk factors measured at 15.4 years, with the exception of a weak inverse association with CRP (-5.5% difference; 95% CI -11.4% to 0.8%). There was no strong evidence of associations with offspring triglycerides, glucose or insulin.
Our findings suggest that fetal exposure to 25(OH)D is unlikely to influence cardiovascular risk factors of individuals later in life.
[Show abstract][Hide abstract] ABSTRACT: Objective
Current methods of risk-stratification in patients with type 2 diabetes are suboptimal. The current study assesses the ability of N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT) to improve the prediction of cardiovascular events and death in patients with type 2 diabetes.Research Design and MethodsA nested case-cohort study was performed in 3,862 patients who participated in the Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation trial.ResultsSeven hundred and nine (18%) patients experienced a major cardiovascular event (composite of cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) and 706 (18%) died during a median of 5 years follow-up. In Cox regression models, adjusting for all established risk predictors, the hazard ratio [HR] for cardiovascular events for NT-proBNP was 1.95 per 1 standard deviation [SD] increase (95% confidence interval [CI] 1.72-2.20) and the HR for hs-cTnT was 1.50 per 1 SD increase (95% CI 1.36-1.65). The HRs for death were 1.97 (95% CI 1.73-2.24) and 1.52 (95% CI 1.37-1.67), respectively. The addition of either marker improved 5-year risk classification for cardiovascular events (net reclassification index in continuous model, 39% for NT-proBNP and 46% for hs-cTnT). Likewise, both markers greatly improved the accuracy with which the 5-year risk of death was predicted. The combination of both markers provided optimal risk discrimination.ConclusionNT-proBNP and hs-cTnT appear to greatly improve the accuracy with which the risk of cardiovascular events or death can be estimated in patients with type 2 diabetes.
[Show abstract][Hide abstract] ABSTRACT: We investigated the association of 2 markers of endothelial dysfunction, tissue plasminogen activator (t-PA) and Von Willebrand factor (VWF), with cerebral blood flow (CBF) in 541 older participants at high risk for cardiovascular disease. Serum levels of t-PA and VWF were measured at baseline. Participants underwent 2 successive brain magnetic resonance imaging scans, first at baseline and the then after a mean follow-up of 33 months. Total CBF was determined in each scan and also standardized for brain parenchymal volume. At baseline, higher t-PA was associated with lower CBF (p = 0.034). In the longitudinal analysis, higher levels of VWF were associated with a steeper decline in CBF (p = 0.043). There was no association between t-PA and decrease in CBF. These associations were independent of sociodemographic and cardiovascular factors. In conclusion, elevated markers of endothelial dysfunction are associated with lower CBF in older adults at risk for cardiovascular disease.
Neurobiology of aging 09/2013; · 5.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Given that the primordial ovarian follicular pool is established in utero, it may be influenced by parental characteristics and the intrauterine environment. Anti-Müllerian hormone (AMH) levels are increasingly recognized as a biomarker of ovarian reserve in females in adulthood and adolescence. We examined and compared associations of maternal and paternal prenatal exposures with AMH levels in adolescent (mean age, 15.4 years) female offspring (n = 1,399) using data from the Avon Longitudinal Study of Parents and Children, a United Kingdom birth cohort study that originated in 1991 and is still ongoing (data are from 1991-2008). The median AMH level was 3.67 ng/mL (interquartile range: 2.46-5.57). Paternal but not maternal smoking prior to and during pregnancy were inversely associated with AMH levels. No or irregular maternal menstrual cycles before pregnancy were associated with higher AMH levels in daughter during adolescence. High maternal gestational weight gain (top fifth versus the rest of the distribution) was associated with lower AMH levels in daughters. Parental age, body mass index, and alcohol intake during pregnancy, child's birth weight, and maternal parity and time to conception were not associated with daughters' AMH levels. Our results suggest that some parental preconceptual characteristics and environmental exposures while the child is in utero may influence the long-term ovarian development and function in female offspring.
American journal of epidemiology 09/2013; · 5.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chloride (Cl(-)) is the major extracellular anion in the body, accompanying sodium (Na(+)), and is primarily derived from dietary sources. Data suggest that increased dietary Cl(-) intake increases blood pressure, yet paradoxically, higher serum Cl(-) appears associated with lower mortality and cardiovascular risk. This implies that serum Cl(-) also reflects risk pathways independent of blood pressure, serum Na(+), and bicarbonate (HCO3(-)). We analyzed 12 968 hypertensive individuals followed up for 35 years, using Cox proportional hazards model to test whether baseline serum Cl(-) was an independent predictor of mortality. To distinguish the effect of Cl(-) from Na(+) and HCO3(-), we adjusted for these electrolytes and also performed the analysis stratified by Na(+)/HCO3(-) and Cl(-) levels. Generalized estimating equation was used to determine the effect of baseline Cl(-) on follow-up blood pressure. The total time at risk was 197 101 person-years. The lowest quintile of serum Cl(-) (<100 mEq/L) was associated with a 20% higher mortality (all-cause, cardiovascular and noncardiovascular) compared with the remainder of the subjects. A 1 mEq/L increase in serum Cl(-) was associated with a 1.5% (hazard ratio, 0.985; 95% confidence interval, 0.98-0.99) reduction in all-cause mortality, after adjustment for baseline confounding variables and Na(+), K(+), and HCO3(-) levels. The group with Na(+)>135 and Cl(-)>100 had the best survival, and compared with this group, the Na(+)>135 and Cl(-)<100 group had significantly higher mortality (hazard ratio, 1.21; 95% confidence interval, 1.11-1.31). Low, not high Serum Cl(-) (<100 mEq/L), is associated with greater mortality risk independent of obvious confounders. Further studies are needed to elucidate the relation between Cl(-) and risk.