Carotid intima media thickness (IMT) progression is increasingly used as a surrogate for vascular risk. This use is supported by data from a few clinical trials investigating statins, but established criteria of surrogacy are only partially fulfilled. To provide a valid basis for the use of IMT progression as a study end point, we are performing a 3-step meta-analysis project based on individual participant data.
Objectives of the 3 successive stages are to investigate (1) whether IMT progression prospectively predicts myocardial infarction, stroke, or death in population-based samples; (2) whether it does so in prevalent disease cohorts; and (3) whether interventions affecting IMT progression predict a therapeutic effect on clinical end points.
Recruitment strategies, inclusion criteria, and estimates of the expected numbers of eligible studies are presented along with a detailed analysis plan.
Genetic determinants of peripheral arterial disease (PAD) remain largely unknown. To identify genetic variants associated with the ankle-brachial index (ABI), a noninvasive measure of PAD, we conducted a meta-analysis of genome-wide association study data from 21 population-based cohorts.
Methods and Results
Continuous ABI and PAD (ABI≤0.9) phenotypes adjusted for age and sex were examined. Each study conducted genotyping and imputed data to the ~2.5 million SNPs in HapMap. Linear and logistic regression models were used to test each SNP for association with ABI and PAD using additive genetic models. Study-specific data were combined using fixed-effects inverse variance weighted meta-analyses. There were a total of 41,692 participants of European ancestry (~60% women, mean ABI 1.02 to 1.19), including 3,409 participants with PAD and with GWAS data available. In the discovery meta-analysis, rs10757269 on chromosome 9 near CDKN2B had the strongest association with ABI (β= −0.006, p=2.46x10−8). We sought replication of the 6 strongest SNP associations in 5 population-based studies and 3 clinical samples (n=16,717). The association for rs10757269 strengthened in the combined discovery and replication analysis (p=2.65x10−9). No other SNP associations for ABI or PAD achieved genome-wide significance. However, two previously reported candidate genes for PAD and one SNP associated with coronary artery disease (CAD) were associated with ABI : DAB21P (rs13290547, p=3.6x10−5); CYBA (rs3794624, p=6.3x10−5); and rs1122608 (LDLR, p=0.0026).
GWAS in more than 40,000 individuals identified one genome-wide significant association on chromosome 9p21 with ABI. Two candidate genes for PAD and 1 SNP for CAD are associated with ABI.
cohort study; genetic association; genome-wide association study; meta-analysis; peripheral vascular disease
Although extracranial internal carotid artery (e-ICA) occlusion is a common pathology in patients undergoing intravenous thrombolysis for treatment of acute ischemic stroke, no data on e-ICA recanalization rate or potential effects on outcome are yet available.
Methods and Results
This study included 52 consecutive patients with e-ICA occlusion and ischemic stroke undergoing standard intravenous thrombolysis. The rate of e-ICA recanalization was 30.8% [95%CI, 18.2–43.3], documented at 3.5 [2.0–11.8] (median [IQR]) days after stroke, as compared to 8.6% [95%CI, 3.5–13.7] in a series of 116 consecutive patients with symptomatic e-ICA occlusion not undergoing thrombolysis (P<0.001 for difference). Functional outcome three months after stroke did not significantly differ for those with or without e-ICA recanalization following intravenous thrombolysis (modified Rankin scale ≤2: 31.3% vs. 22.2%, odds ratio 1.6 [95%CI, 0.4–5.9], P = 0.506). In patients with e-ICA occlusion of atherothrombotic origin, recanalization resulted in most instances in residual high-grade stenosis (13 of 14).
Recanalization of e-ICA occlusion after stroke thrombolysis occurred in about one third of patients. Although e-ICA recanalization had no significant effect on patient outcome, control sonography in the early days after thrombolysis is recommended for the detection of potential residual e-ICA stenosis.
Childhood and adolescent overweight, defined by body mass index (BMI) are associated with an increased risk of cardiovascular disease in later life. Abdominal adiposity may be more important in associations with cardiovascular diseases but waist circumference (WC) has been rarely studied in children. We studied associations between BMI and WC and blood pressure (BP) and cholesterol in 12-year-old children and prospectively changes in BMI or WC status between age 8 and 12 years and BP and cholesterol at age 12.
Weight, height, WC, BP and cholesterol concentrations were measured in 1432 children at age 12 years. Linear regression was used to study the associations between high BMI and large WC (>90th percentile) and BP and cholesterol.
Systolic BP was 4.9 mmHg higher (95% (CI 2.5, 7.2) in girls and 4.2 mmHg (95%CI 1.9, 6.5) in boys with a high BMI. Large WC was also associated with higher systolic BP in girls (3.7 mmHg (95%CI 1.3, 6.1)) and boys (3.5 mmHg (95%CI 1.2, 5.8)). Diastolic BP and cholesterol concentrations were significantly positively (HDL cholesterol negatively) associated with high BMI and large WC, too. Normal weight children with a history of overweight did not have higher blood pressure levels or adverse cholesterol concentrations than children that were normal weight at both ages.
A high BMI and large WC were associated with higher BP levels and adverse cholesterol concentrations. WC should be taken into account when examining cardiovascular risk factors in children.
Circulating levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble P-selectin (sP-selectin), and soluble E-selectin (sE-selectin) have been associated with variation at the ABO locus. To evaluate these associations and the effect sizes, we performed a meta-analysis with new and previous reported data for polymorphism rs579459.
Methods and Results
Compared with major allele homozygotes, heterozygotes and minor allele homozygotes had 4.6% (95%CI=3.4–5.8%, p=7.3×10−14) and 7.2% (95%CI=4.7–9.7%, p=1.5×10−8), respectively, lower sICAM-1 levels (n=33,671). An allele dose dependent association also was observed for sP-selectin (n=4,921), with heterozygotes and minor allele homozygotes having 11.5% (95%CI=7.2–15.8%, p=1.7×10−7) and 18.6% (95%CI=9.1–28.1%, p=1.2×10−4), respectively, lower levels than in major allele homozygotes. A larger effect size, again consistent with an additive genetic model, was seen for sE-selectin (n=2,860) whose level was 25.6% (95%CI=19.0–32.2%, p=2.1×10−14) lower in heterozygotes and 43.3% (95%CI=36.9–49.3%, p=4.3×10−42) lower in minor allele homozygotes, than in major allele homozygotes.
The data support the association of variation at the ABO locus with sICAM-1, sP-selectin and sE-selectin levels.
Cell adhesion molecules; plasma; genetics; cardiovascular disease
Ascending aortic aneurysm is a connective tissue disorder. Even though multiple novel gene mutations have been identified, risk profiling and diagnosis before rupture still represent a challenge. There are studies demonstrating shorter telomere lengths in the blood leukocytes of abdominal aortic aneurysm patients. The aim of this study was to measure whether relative telomere lengths are changed in the blood leukocytes of ascending aortic aneurysm patients. We also studied the expression of telomerase in aortic tissue samples of ascending aortic aneurysms. Relative lengths of leukocyte telomeres were determined from blood samples of patients with ascending aortic aneurysms and compared with healthy controls. Telomerase expression, both at the level of mRNA and protein, was quantified from the aortic tissue samples. Mean relative telomere length was significantly longer in ascending aortic aneurysm blood samples compared with controls (T/S ratio 0.87 vs. 0.61, p<0.001). Expressions of telomerase mRNA and protein were elevated in the aortic aneurysm samples (p<0.05 and p<0.01). Our study reveals a significant difference in the mean length of blood leukocyte telomeres in ascending aortic aneurysm and controls. Furthermore, expression of telomerase, the main compensating factor for telomere loss, is elevated at both the mRNA and protein level in the samples of aneurysmal aorta. Further studies will be needed to confirm if this change in telomere length can serve as a tool for assessing the risk of ascending aortic aneurysm.
Epicardial adipose tissue (EAT) is an active metabolic and endocrine organ. Previous studies focusing mainly on patients with preserved left ventricular function (LVF) could show a correlation between increased amounts of EAT and the extent and activity of coronary artery disease (CAD). However, to date, there are no data available about the relationship between EAT and the severity of CAD with respect to the whole spectrum of LVF impairment. Therefore, we evaluated this relationship in patients with CAD.
250 patients with CAD and 50 healthy controls underwent CMR examination to assess EAT. The severity of CAD was defined using the angiographic Gensini score (GSS).
The GSS ranged from 2–364. Linear regression analysis revealed a significant correlation between EAT and GSS (r = 0.177, p = 0.01). Patients with mild (GSS≤10) and moderate CAD (GSS>10−≤40) showed comparable EAT to healthy controls. However, in patients with severe CAD (GSS>40) EAT was significantly reduced (p<0.0001) compared to healthy controls. Interestingly, patients with the same GSS revealed different EAT depending on the left ventricular function (LVF). Patients with preserved LVF (LVF≥50%) showed more EAT mass compared to those with reduced LVF (LVF<50%) regardless of the GSS. In patients with preserved LVF and mild CAD, EAT was comparable to healthy controls (61.8±19.4 g vs. 62.9±14.4 g, p = 0.8). In patients with moderate CAD, EAT rose significantly to 83.1±24.9 g (p = 0.01) and started to decline to 66.4±23.6 g in patients with severe CAD (p = 0.03). Contrary, in CAD patients with reduced LVF, EAT was already significantly reduced in patients with mild CAD as compared to healthy controls (p = 0.001) and showed a stepwise decline with increasing CAD severity.
The relationship between EAT and the severity of CAD depends on LVF. These findings emphasize the multifactorial interaction between EAT and the severity of CAD.
Vitamin K is essential for activation of γ-carboxyglutamate (Gla)-proteins including the vascular calcification inhibitor matrix Gla-protein (MGP). Insufficient vitamin K intake leads to production of uncarboxylated, mostly inactive proteins and contributes to an increased cardiovascular risk. In kidney transplant recipients, cardiovascular risk is high but vitamin K intake and status have not been defined. We investigated dietary vitamin K intake, vascular vitamin K status and its determinants in kidney transplant recipients. We estimated vitamin K intake in a cohort of kidney transplant recipients (n = 60) with stable renal function (creatinine clearance 61 [42–77] (median [interquartile range]) ml/min), who were 75 [35–188] months after transplantation, using three-day food records and food frequency questionnaires. Vascular vitamin K status was assessed by measuring plasma desphospho-uncarboxylated MGP (dp-ucMGP). Total vitamin K intake was below the recommended level in 50% of patients. Lower vitamin K intake was associated with less consumption of green vegetables (33 vs 40 g/d, p = 0.06) and increased dp-ucMGP levels (621 vs 852 pmol/L, p<0.05). Accordingly, dp-ucMGP levels were elevated (>500 pmol/L) in 80% of patients. Multivariate regression identified creatinine clearance, coumarin use, body mass index, high sensitivity-CRP and sodium excretion as independent determinants of dp-ucMGP levels. In a considerable part of the kidney transplant population, vitamin K intake is too low for maximal carboxylation of vascular MGP. The high dp-ucMGP levels may result in an increased risk for arterial calcification. Whether increasing vitamin K intake may have health benefits for kidney transplant recipients should be addressed by future studies.
Shorter telomere length and poor sleep are more prevalent at older ages, but their relationship is uncertain. This study explored associations between sleep duration and telomere length in a sample of healthy middle and early old age people.
Participants were 434 men and women aged 63.3 years on average drawn from the Whitehall II cohort study. Sleep duration was measured by self-report.
There was a linear association between sleep duration and leukocyte telomere length in men but not in women (P = 0.035). Men reporting shorter sleep duration had shorter telomeres, independently of age, body mass index, smoking, educational attainment, current employment, cynical hostility scores and depressive symptoms. Telomeres were on average 6% shorter in men sleeping 5 hours or fewer compared with those sleeping more than 7 hours per night.
This study adds to the growing literature relating sleep duration with biomarkers of aging, and suggests that shortening of telomeres might reflect mechanisms through which short sleep contributes to pathological conditions in older men.
The association between white blood cell (WBC) count and coronary artery disease (CAD) is unknown in young adults. Our objective was to assess the association between WBC count and its changes over time with CAD incidence in the Metabolic, Life-style and Nutrition Assessment in Young adults (MELANY) study, a cohort of Israeli army personnel.
Methods and Findings
29,120 apparently healthy young men (mean age; 31.2±5.5 years) with a normal baseline WBC count (3,000–12,000 cells/mm3) were followed during a mean follow up of 7.5±3.8 years for incidence of CAD. Participants were screened every 3–5 years using a stress test, and CAD was confirmed by coronary angiography. In a multivariate model adjusted for age, body mass index (BMI), LDL- and HDL-cholesterol, blood pressure, family history of CAD, physical activity, diabetes, triglycerides and smoking status, WBC levels (divided to quintiles) above 6,900 cells/mm3 (quintile 4) were associated with a 2.17-fold increase (95%CI = 1.18–3.97) in the risk for CAD as compared with men in quintile 1 (WBC≤5,400 cells/mm3). When modeled as a continuous variable, a WBC increment of 1000 cells/mm3 was associated with a 17.4% increase in CAD risk (HR 1.174; 95%CI = 1.067–1.290, p = 0.001). A decrease in the WBC level (within the normal range) during the follow-up period was associated with increased physical activity and decreased triglyceride levels as well as with reduced incidence of CAD.
WBC count is an independent risk factor for CAD in young adults at values well within the normal range. WBC count may assist in detecting subgroups of young men at either low or high risk for progression to CAD.
To test the inflammatory origin of cardiovascular disease, as opposed to its origin in western lifestyle. Population-based assessment of the prevalences of cardiovascular risk factors and cardiovascular disease in an inflammation-prone African population, including electrocardiography and ankle-arm index measurement. Comparison with known prevalences in American and European societies.
Traditional population in rural Ghana, characterised by adverse environmental conditions and a high infectious load. Population-based sample of 924 individuals aged 50 years and older. Median values for cardiovascular risk factors, including waist circumference, BMI, blood pressure, and markers of glucose and lipid metabolism and inflammation. Prevalence of myocardial infarction detected by electrocardiography and prevalence of peripheral arterial disease detected by ankle-arm index. When compared to western societies, we found the Ghanaians to have more proinflammatory profiles and less cardiovascular risk factors, including obesity, dysglycaemia, dyslipidaemia, and hypertension. Prevalences of cardiovascular disease were also lower. Definite myocardial infarction was present in 1.2% (95%CI: 0.6 to 2.4%). Peripheral arterial disease was present in 2.8% (95%CI: 1.9 to 4.1%).
Taken together, our data indicate that for the pathogenesis of cardiovascular disease inflammatory processes alone do not suffice and additional factors, probably lifestyle-related, are mandatory.
The inflammatory biomarker YKL-40 seems to play a role in atherosclerosis and is elevated in patients with obesity, cardiovascular disease and type 2 diabetes. Single nucleotide polymorphisms (SNPs) of the YKL-40 encoding gene, CHI3L1, are associated with inter-individual YKL-40 levels. One study has described an association between a promoter polymorphism of CHI3L1 and levels of low density lipoprotein. The objective of this study was to evaluate the influence of YKL-40 on lipid parameters by determining the association between polymorphisms of CHI3L1, serum YKL-40 and levels of the differentiated lipid profile in a Danish general population.
12 SNPs of CHI3L1 were genotyped, and serum YKL-40 and parameters of the lipid profile were measured in 2,656 Danes. Lipid profile and genotypes were available in another Danish population (n = 6,784) for replication. Cholesterol and triglyceride levels increased with increasing YKL-40 quartile (both p<0.0001), and YKL-40 correlated with triglyceride levels (β = 0.15, p<0.0001). Low density lipoprotein levels increased slightly from the 1st to the 3rd quartile (p = 0.006). The highest YKL-40 quartile was associated with a greater risk of hypercholesterolemia compared to the lowest YKL-40 quartile (odds ratio 1.36, p = 0.009). Minor homozygosity of rs12123883 was associated with higher triglyceride levels (p = 0.022) and a higher prevalence of low high density lipoprotein (p = 0.012), but these associations could not be confirmed in the replication population.
Serum YKL-40 correlates with triglyceride levels in a representative group of the general Danish population. No consistent associations between SNPs of CHI3L1 and lipid levels could be documented.
We assessed the prospective association of resting heart rate (RHR) at baseline with peak oxygen uptake (VO2peak) 23 years later, and evaluated whether physical activity (PA) could modify this association.
Both RHR and VO2peak are strong and independent predictors of cardiovascular morbidity and mortality. However, the association of RHR with VO2peak and modifying effect of PA have not been prospectively assessed in population studies.
In 807 men and 810 women free from cardiovascular disease both at baseline (1984–86) and follow-up 23 years later, RHR was recorded at both occasions, and VO2peak was measured by ergospirometry at follow-up. We used Generalized Linear Models to assess the association of baseline RHR with VO2peak, and to study combined effects of RHR and self-reported PA on later VO2peak.
There was an inverse association of RHR at baseline with VO2peak (p<0.01). Men and women with baseline RHR greater than 80 bpm had 4.6 mL·kg−1·min−1 (95% confidence interval [CI], 2.8 to 6.3) and 1.4 mL·kg−1·min−1 (95% CI, −0.4 to 3.1) lower VO2peak at follow-up compared with men and women with RHR below 60 bpm at baseline. We found a linear association of change in RHR with VO2peak (p = 0.03), suggesting that a decrease in RHR over time is likely to be beneficial for cardiovascular fitness. Participants with low RHR and high PA at baseline had higher VO2peak than inactive people with relatively high RHR. However, among participants with relatively high RHR and high PA at baseline, VO2peak was similar to inactive people with relatively low RHR.
RHR is an important predictor of VO2peak, and serial assessments of RHR may provide useful and inexpensive information on cardiovascular fitness. The results suggest that high levels of PA may compensate for the lower VO2peak associated with a high RHR.
We hypothesized that hidden malignancy could be detected in patients with cryptogenic stroke without active cancer when they showed the distinctive characteristics of cancer-related stroke.
Methods and Findings
Among 2,562 consecutive patients with acute ischemic stroke, patients with cryptogenic stroke were analyzed and categorized into two groups according to the presence of active cancer: cryptogenic stroke with active cancer (cancer-related stroke, CA-stroke) group and without active cancer (CR-stroke) group. Patients with active lung cancer without stroke were also recruited for comparison purposes (CA-control). Clinical factors, lesion patterns on diffusion-weighted MRI (DWI), and laboratory findings were analyzed among groups. A total of 348 patients with cryptogenic stroke were enrolled in this study. Among them, 71 (20.4%) patients had active cancer at the time of stroke. The D-dimer levels were significantly higher in patients with CA-stroke than those with CR-stroke or CA-control (both p<0.001). Regarding lesion patterns, patients with CA-stroke mostly had multiple lesions in multiple vascular territories, while more than 80% of patients with CR-stroke had single/multiple lesions in a single vascular territory (P<0.001). D-dimer levels (OR 1.11 per 1 µg/mL increase; 95% CI 1.06–1.15; P<0.001) and DWI lesion patterns (OR 7.13; 95% CI 3.42–14.87; P<0.001) were independently associated with CA-stroke. Workup for hidden malignancy was performed during hospitalization in 10 patients who showed elevated D-dimer levels and multiple infarcts involving multiple vascular territories but had no known cancer, and it revealed hidden malignancies in all the patients.
Patients with CA-stroke have distinctive D-dimer levels and lesion patterns. These characteristics can serve as clues to occult cancer in patients with cryptogenic stroke.
People with epilepsy are at increased risk for sudden death. The most prevalent cause of sudden death in the general population is sudden cardiac arrest (SCA) due to ventricular fibrillation (VF). SCA may contribute to the increased incidence of sudden death in people with epilepsy. We assessed whether the risk for SCA is increased in epilepsy by determining the risk for SCA among people with active epilepsy in a community-based study.
Methods and Results
This investigation was part of the Amsterdam Resuscitation Studies (ARREST) in the Netherlands. It was designed to assess SCA risk in the general population. All SCA cases in the study area were identified and matched to controls (by age, sex, and SCA date). A diagnosis of active epilepsy was ascertained in all cases and controls. Relative risk for SCA was estimated by calculating the adjusted odds ratios using conditional logistic regression (adjustment was made for known risk factors for SCA). We identified 1019 cases of SCA with ECG-documented VF, and matched them to 2834 controls. There were 12 people with active epilepsy among cases and 12 among controls. Epilepsy was associated with a three-fold increased risk for SCA (adjusted OR 2.9 [95%CI 1.1–8.0.], p = 0.034). The risk for SCA in epilepsy was particularly increased in young and females.
Epilepsy in the general population seems to be associated with an increased risk for SCA.
Both anaemia and cardiovascular disease (CVD) are common in people with diabetes. While individually both characteristics are known to raise mortality risk, their combined influence has yet to be quantified. In this pooling project, we examined the combined impact of baseline haemoglobin levels and existing CVD on all-cause and CVD mortality in people with diabetes. We draw comparison of these effects with those apparent in diabetes-free individuals.
A combined analyses of 7 UK population-based cohorts resulted in 26,480 study members. There were 946 participants with physician-diagnosed diabetes, 2227 with anaemia [haemoglobin<13 g/dl (men) or <12 (women)], 2592 with existing CVD (stroke, ischaemic heart disease), and 21,396 with none of the conditions. Across diabetes and anaemia subgroups, and using diabetes-free, non-anaemic participants as the referent group, the adjusted hazard ratios (HR) were 1.46 (95% CI: 1.30–1.63) for anaemia, 1.67 (1.45–1.92) for diabetes, and 2.10 (1.55–2.85) for diabetes and anaemia combined. Across combined diabetes, anaemia and CVD subgroups, and compared with non-anaemic, diabetes-free and CVD-free participants, HR (95% CI) for all-cause mortality were 1.49 (1.32–1.69) anaemia, 1.60 (1.46–1.76) for existing CVD, and 1.66 (1.39–1.97) for diabetes alone. Equivalents were 2.13 (1.48–3.07) for anaemia and diabetes, 2.68 (2.14–3.36) for diabetes and existing CVD, and 3.25 (1.88–5.62) for the three combined. Patterns were similar for CVD mortality.
Individually, anaemia and CVD confer similar mortality risks in people with diabetes, and are excessively fatal in combination. Screening for anaemia would identify vulnerable diabetic patients whose outcomes can potentially be improved.
To investigate the natural history of carotid atherosclerosis in patients who experienced a TIA or ischemic stroke.
Patients and Methods
Ninety-two TIA/stroke patients (57 men, mean age 67.7±9.8 years) with ipsilateral <70% carotid stenosis underwent multisequence MRI of the plaque ipsilateral to the symptomatic side at baseline and after one year. For each plaque, several parameters were assessed at both time points.
Carotid lumen, wall and total vessel ( = carotid lumen and wall) volume did not significantly change. Forty-four patients had a plaque with a lipid-rich necrotic core (LRNC) at baseline, of which 34 also had a LRNC after one year. In three patients a LRNC appeared after one year. Thirty patients had a plaque with a thin and/or ruptured fibrous cap (FC) at both time points. In seven patients, FC status changed from thin and/or ruptured into thick and intact. In three patients, FC status changed from thick and intact into thin and/or ruptured. Twenty patients had intraplaque hemorrhage (IPH) at both time points. In four patients, IPH disappeared, whereas in three patients, new IPH appeared at follow-up.
In TIA/stroke patients, carotid plaque morphology does not significantly change over a one-year period. IPH and FC status change in a minority of patients.
Psychological stress is suggested to accelerate the rate of biological aging. We investigated whether work-related exhaustion, an indicator of prolonged work stress, is associated with accelerated biological aging, as indicated by shorter leukocyte telomeres, that is, the DNA-protein complexes that cap chromosomal ends in cells.
We used data from a representative sample of the Finnish working-age population, the Health 2000 Study. Our sample consisted of 2911 men and women aged 30–64. Work-related exhaustion was assessed using the Maslach Burnout Inventory - General Survey. We determined relative leukocyte telomere length using a quantitative real-time polymerase chain reaction (PCR) -based method.
After adjustment for age and sex, individuals with severe exhaustion had leukocyte telomeres on average 0.043 relative units shorter (standard error of the mean 0.016) than those with no exhaustion (p = 0.009). The association between exhaustion and relative telomere length remained significant after additional adjustment for marital and socioeconomic status, smoking, body mass index, and morbidities (adjusted difference 0.044 relative units, standard error of the mean 0.017, p = 0.008).
These data suggest that work-related exhaustion is related to the acceleration of the rate of biological aging. This hypothesis awaits confirmation in a prospective study measuring changes in relative telomere length over time.
Whether a healthy lifestyle may be associated with longer telomere length is largely unknown.
To examine healthy lifestyle practices, which are primary prevention measures against major age-related chronic diseases, in relation to leukocyte telomere length.
Design and Setting
Cross-sectional analysis in the Nurses' Health Study (NHS).
The population consisted of 5,862 women who participated in multiple prospective case-control studies within the NHS cohort. Z scores of leukocyte telomere length were derived within each case-control study. Based on prior work, we defined low-risk or healthy categories for five major modifiable factors assessed in 1988 or 1990: non-current smoking, maintaining a healthy body weight (body mass index in 18.5–24.9 kg/m2), engaging in regular moderate or vigorous physical activities (≥150 minutes/week), drinking alcohol in moderation (1 drink/week to <2 drinks/day), and eating a healthy diet (Alternate Healthy Eating Index score in top 50%). We calculated difference (%) of the z scores contrasting low-risk groups with reference groups to evaluate the association of interest.
Although none of the individual low-risk factors was significantly associated with larger leukocyte telomere length z scores, we observed a significant, positive relationship between the number of low-risk factors and the z scores. In comparison with women who had zero low-risk factors (1.9% of the total population) and were, therefore, considered the least healthy group, the leukocyte telomere length z scores were 16.4%, 22.1%, 28.7%, 22.6%, and 31.2% (P for trend = 0.015) higher for women who had 1 to 5 low-risk factors, respectively.
Adherence to a healthy lifestyle, defined by major modifiable risk factors, was associated with longer telomere length in leukocytes.
C-reactive Protein (CRP) measurements above 10 mg/L have been conventionally treated as acute inflammation and excluded from epidemiologic studies of chronic inflammation. However, recent evidence suggest that such CRP elevations can be seen even with chronic inflammation. The authors assessed 3,300 participants in The Coronary Artery Risk Development in Young Adults study, who had two or more CRP measurements between 1992/3 and 2005/6 to a) investigate characteristics associated with repeated CRP elevation above 10 mg/L; b) identify subgroups at high risk of repeated elevation; and c) investigate the effect of different CRP thresholds on the probability of an elevation being one-time rather than repeated. 225 participants (6.8%) had one-time and 103 (3.1%) had repeated CRP elevation above 10 mg/L. Repeated elevation was associated with obesity, female gender, low income, and sex hormone use. The probability of an elevation above 10 mg/L being one-time rather than repeated was lowest (51%) in women with body mass index above 31 kg/m2, compared to 82% in others. These findings suggest that CRP elevations above 10 mg/L in obese women are likely to be from chronic rather than acute inflammation, and that CRP thresholds above 10 mg/L may be warranted to distinguish acute from chronic inflammation in obese women.
Leukocyte telomere length (TL) is considered a biomarker for biological aging. Shortened TL has been observed in many complex diseases, including type 2 diabetes (T2DM). Lifestyle intervention studies, e.g. the Diabetes Prevention Study (DPS), have shown a decrease in the incidence of T2DM by promoting healthy lifestyles in individuals with impaired glucose tolerance (IGT). Our aim was to study in the DPS the influence of the lifestyle intervention on TL. TL was measured by quantitative PCR-based method at two time points (N = 334 and 343) on average 4.5 years apart during the active intervention and post-intervention follow-up. TL inversely correlated with age. Our main finding was that TL increased in about two thirds of the individuals both in the intervention and in the control groups during follow-up; TL increased most in individuals with the shortest TL at the first measurement. TL was not associated with development of T2DM, nor did lifestyle intervention have an effect on TL. No association between insulin secretion or insulin resistance indices and TL was observed. We did not detect an association between TL and development of T2DM in the DPS participants. It could be due to all participants being overweight and having IGT at baseline, both of which have been found to be independently associated with shorter leukocyte TL in some earlier studies. TL had no substantial role in worsening of glucose tolerance in people with IGT. Our study confirms that leukocyte TL can increase with time even in obese people with impaired glucose metabolism.
Glycosylated hemoglobin (HbA1c) recently has been recommended for the diagnosis of diabetes by the American Diabetes Association, but its value in the prediction of type 2 diabetes is poorly understood. In this study we evaluated how high-normal HbA1c levels predict type 2 diabetes.
RESEARCH DESIGN AND METHODS
We measured HbA1c in 919 Caucasian subjects, aged 40–79 years, and recorded new cases of type 2 diabetes in the following 15 years. Diabetes was diagnosed with HbA1c.
Subjects were stratified according to baseline HbA1c (<5.0, 5.00–5.49 [reference], 5.50–5.99, and 6.00–6.49%). Sex- and age-adjusted hazard ratios (95% CI) for type 2 diabetes were 1.11 (0.30–4.41), 1.00, 3.79 (1.79–8.06), and 12.50 (5.51–28.34), respectively. Results did not change after adjusting for several putative confounding factors and were confirmed when models with updated variables were used.
HbA1c is an independent risk factor for type 2 diabetes. Subjects with high-normal levels of HbA1c deserve particular attention because they have a strong risk of developing diabetes.
Stroke contributes significantly to disability and mortality in developing countries yet little is known about the determinants of stroke outcomes in such countries. 12% of Malawian adults have HIV/AIDS. It is not known whether having HIV-infection alters the outcome of stroke. The aim of this study was to document the functional outcome and mortality at 1 year of first-ever acute stroke in Malawi. Also to find out if the baseline variables, including HIV-infection, affect the outcome of stroke.
Methods and Findings
147 adult patients with first-ever acute stroke were prospectively followed up for 12 months. Conventional risk factors and HIV-infection were assessed at baseline. Stroke severity was evaluated with modified National Institute of Health Stroke Scale (mNIHSS) and functional outcome with modified Rankin scale (mRS). Fifty (34%) of patients were HIV-seropositive. 53.4% of patients had a poor outcome (severe disability or death, mRS 4–6) at 1 year. Poor outcome was related to stroke severity and female gender but not to presence of HIV-infection. HIV-seropositive patients were younger and had less often common risk factors for stroke. They suffer more often ischemic stroke than HIV-seronegative patients.
Mild stroke and male gender were associated with favourable outcome. HIV-infection is common in stroke patients in Malawi but does not worsen the outcome of stroke. However, it may be a risk factor for ischemic stroke for young people, who do not have the common stroke risk factors. Our results are significant, because stroke outcome in HIV-seropositive patients has not been studied before in a setting such as ours, with very limited resources and a high prevalence of HIV.
Falls are common in older people and increase in prevalence with advancing old age. There is limited knowledge about their impact in those aged 85 years and older, the fastest growing age group of the population. We investigated the prevalence and impact of falls, and the overlap between falls, dizziness and blackouts, in a population-based sample of 85 year olds.
Design: Cross-sectional analysis of baseline data from Newcastle 85+ Cohort Study. Setting: Primary care, North-East England. Participants: 816 men and women aged 85 years. Measurements: Structured interview with research nurse. Cost-consequence analysis of fall-related healthcare costs.
Over 38% (313/816) of participants had fallen at least once in the previous 12 months and of these: 10.6% (33/312) sustained a fracture, 30.1% (94/312) attended an emergency department, and 12.8% (40/312) were admitted to hospital. Only 37.2% (115/309) of fallers had specifically discussed their falls problem with their general practitioner and only 12.7% (39/308) had seen a falls specialist. The average annual healthcare cost per faller was estimated at £202 (inter-quartile range £174–£231) or US$329 ($284–$377). ‘Worry about falling’ was experienced by 42.0% (128/305) of fallers, ‘loss of confidence’ by 40.0% (122/305), and ‘going out less often’ by 25.9% (79/305); each was significantly more common in women, odds ratios (95% confidence interval) for women: men of 2.63 (1.45–4.55), 4.00 (2.27–7.14), and 2.86 (1.54–5.56) respectively. Dizziness and blackouts were reported by 40.0% (318/796) and 6.4% (52/808) of participants respectively. There was marked overlap in the report of falls, dizziness and blackouts.
Falls in 85 year olds are very common, associated with considerable psychological and physical morbidity, and have high impact on healthcare services. Wider use of fall prevention services is needed. Significant expansion in acute and preventative services is required in view of the rapid growth in this age group.
Tooth loss is associated with increased cardiovascular disease (CVD) mortality risk. This association may however be due to residual confounding. We aimed to assess whether tooth loss is associated with specific CVD mortality endpoints in a national population sample adjusting for potential confounders.
Methods and Results
We used a prospective cohort design and data from the Scottish Health Survey. We combined data from surveys in 1995, 1998, 2003 and linked this to mortality records. Dental status was classified through self-reports as natural teeth only, natural teeth and dentures, and no natural teeth (edentate). Cox proportional hazards models were used to estimate risk of CVD mortality by dental status adjusting for potential confounders. The sample consisted of 12871 participants. They were followed for 8.0 (SD: 3.3) years. During 103173 person-years, there were 1480 cases of all-cause mortality, 498 of CVD, and 515 of cancer. After adjusting for demographic, socio-economic, behavioural and health status, edentate subjects had significantly higher risk of all-cause (HR, 1.30; 95% CI, 1.12,1.50) and CVD mortality (HR, 1.49; 95% CI, 1.16,1.92) compared to subjects with natural teeth only. Dental status was not significantly associated with cancer mortality in fully adjusted analysis. Further analysis for CVD mortality showed that in the fully adjusted model, edentate subjects had 2.97 (95% CI, 1.46, 6.05) times higher risk for stroke-related mortality.
In a national population sample of Scottish adults, being edentate was an independent predictor of total CVD mortality, although this was mainly driven by fatal stroke events.