Experimental studies suggest long-chain n-3 polyunsaturated fatty acids (n-3 PUFA) may reduce risk of atrial fibrillation (AF). Prior studies evaluating fish or n-3 PUFA consumption from dietary questionnaires and incident AF have been conflicting. Circulating levels of n-3 PUFA provide an objective measurement of exposure.
Methods and Results
Among 3,326 US men and women age≥65y and free of AF or heart failure at baseline, plasma phospholipid levels of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and docosahexaenoic acid (DHA) were measured at baseline using standardized methods. Incident AF (789 cases) was prospectively identified from hospital discharge records and study visit electrocardiograms during 31,169 person-years of follow-up (1992-2006). In multivariable Cox models adjusted for other risk factors, the RR in the top versus lowest quartile of total n-3 PUFA (EPA+DPA+DHA) levels was 0.71 (95%CI=0.57-0.89, P-trend=0.004); and of DHA levels, 0.77 (95%CI=0.62-0.96, P-trend=0.01). EPA and DPA levels were not significantly associated with incident AF. Evaluated non-parametrically, both total n-3 PUFA and DHA showed graded and linear inverse associations with incidence of AF. Adjustment for intervening events such as heart failure or myocardial infarction during follow-up did not appreciably alter results.
In older adults, higher circulating total long-chain n-3 PUFA and DHA levels were associated with lower risk of incident AF. These results highlight the need to evaluate whether increased dietary intake of these fatty acids could be effective for primary prevention of AF.
atrial fibrillation; biomarkers; epidemiology; fatty acids
Atrial fibrillation (AF) is a common and costly problem among older persons. The frequency of AF increases with age, but representative national data about incidence and prevalence are limited. We examined the annual incidence, prevalence, and mortality associated with AF among older persons.
Methods and Results
In a retrospective cohort study of Medicare beneficiaries 65 years and older diagnosed with AF between 1993 and 2007, we measured annual age- and sex-adjusted incidence and prevalence of AF and mortality following an AF diagnosis. Among 433,123 patients with incident AF, the mean age was 80 years, 55% were women, and 92% were white. The incidence of AF remained steady during the 14-year study period, ranging from 27.3 to 28.3 per 1000 person-years. Incidence rates were consistently higher among men and white beneficiaries. The prevalence of AF increased across the study period (mean, 5% per year) and was robust to sensitivity analyses. Among beneficiaries with incident AF in 2007, 36% had heart failure, 84% had hypertension, 30% had cerebrovascular disease, and 8% had dementia. Mortality after AF diagnosis declined slightly over time but remained high. In 2007, the age- and sex-adjusted mortality rates were 11% at 30 days and 25% at 1 year.
Among older Medicare beneficiaries, incident AF is common and has remained relatively stable for more than a decade. Incident AF is associated with significant comorbidity and mortality; death occurs in one-quarter of beneficiaries within 1 year.
atrial fibrillation; mortality; outcome assessment (health care)
Background and purpose
Few studies have assessed post-glucose load measures of insulin resistance and ischemic stroke risk, and data are sparse for older adults. We investigated whether fasting and post-glucose load measures of insulin resistance were related to incident ischemic stroke in non-diabetic older adults.
Participants were men and women in the Cardiovascular Health Study, aged 65+ and without prevalent diabetes or stroke at baseline, followed for 17 years for incident ischemic stroke. The Gutt insulin sensitivity index was calculated from baseline body weight and fasting and 2-hour post-load insulin and glucose; a lower Gutt index indicates higher insulin resistance.
Analyses included 3,442 participants (42% men) with a mean age of 73. Incidence of ischemic stroke was 9.8 strokes per 1,000 person years. The relative risk (RR) for lowest quartile vs. highest quartile of Gutt index was 1.64 (95% confidence interval: 1.24, 2.16), adjusted for demographics and prevalent cardiovascular and kidney disease. Similarly, the adjusted RR for highest quartile vs. lowest quartile of 2-hour glucose was 1.84 (95% CI: 1.39, 2.42). In contrast, the adjusted RR for highest quartile vs. lowest quartile of fasting insulin was 1.10 (95% CI: 0.84, 1.46).
In non-diabetic older adults, insulin resistance measured by Gutt index or 2-hour glucose, but not fasting insulin, was associated with risk of incident ischemic stroke.
Non-diabetic older adults; Cohort study; Gutt insulin sensitivity index
Depression is the most common psychiatric disorder in patients with chronic kidney disease (CKD). We sought to determine the association of major depression with mortality among diabetic patients with late stage CKD.
The Pathways Study is a longitudinal, prospective cohort study initiated to determine the impact of depression on outcomes among primary care diabetic patients. Subjects were followed from 2001 until 2007 for a mean duration of 4.4 years. Major depression, identified by the Patient Health Questionnaire-9 (PHQ-9), was the primary exposure of interest. Stage 5 CKD was determined by dialysis codes and estimated glomerular filtration rate (<15ml/min). An adjusted Cox proportional hazards multivariable model was used to determine the association of baseline major depression with mortality.
Of the 4128 enrolled subjects, 110 were identified with stage 5 CKD at baseline. Of those, 34 (22.1%) had major depression. Over a period of 5 years, major depression was associated with 2.95-fold greater risk of death (95% CI=1.24–7.02) compared to those with no or few depressive symptoms.
Major depression at baseline was associated with a 3-fold greater risk of mortality among stage 5 CKD diabetic patients. Given the high mortality risk, further testing of targeted depression interventions should be considered in this population.
Depression; diabetes; mortality; chronic kidney disease; ESRD
rhabdomyolysis; statins; adverse drug reaction; natural language processing
Atrial fibrillation may increase dementia risk, but prior studies yielded conflicting results. Many had low power or limited measures of dementia. We investigated whether atrial fibrillation is associated with increased risk of incident dementia or Alzheimer disease, beyond its effect on stroke.
A prospective cohort study
An integrated healthcare delivery system
A population-based sample of 3,045 community-dwelling adults age 65 and older without dementia or clinical stroke, followed from 1994-2008.
Atrial fibrillation was identified from health plan electronic data using International Classification of Diseases, version 9, codes from inpatient and outpatient encounters. Covariates came from self-report, study measures, and health plan data. Participants were screened every 2 years with the Cognitive Abilities Screening Instrument (score range, 0-100), with detailed neuropsychological and clinical assessment of those scoring less than 86. The outcomes of all-cause dementia and possible or probable Alzheimer disease were determined by a multidisciplinary consensus committee using standard research criteria.
Atrial fibrillation was present in 132/3,045 (4.3%) participants at baseline and was diagnosed in 370 (12.2%) more over a mean of 6.8 years of follow-up. 572 participants (18.8%) developed dementia (449 with Alzheimer disease). The adjusted hazard ratio for all-cause dementia associated with atrial fibrillation was 1.38 (95% CI 1.10-1.73) and for possible or probable Alzheimer disease, 1.50 (95% CI 1.16-1.94). Results were similar for participants with or without clinically recognized stroke during follow-up and in sensitivity analyses examining only probable Alzheimer disease.
Atrial fibrillation is associated with higher risk of developing Alzheimer disease and dementia. Future studies should examine whether specific treatments including optimal anticoagulation can decrease this risk.
atrial fibrillation; cardiac arrhythmia; dementia; Alzheimer disease; epidemiology
Several studies have reported that taller individuals are at greater risk of venous thromboembolism (VTE). We hypothesized that longer leg length would be positively associated with incident VTE, and would explain the height association. LITE ascertained VTE in a prospective population-based sample of 21,860 individuals aged 45 and older. Leg length was measured as standing height minus sitting height. Cox regression models were adjusted for age, race, sex, waist circumference, diabetes, and factor VIII. To evaluate whether leg length was associated with VTE risk independent of height we standardized leg length and height per 1 standard deviation (SD), and then included them simultaneously in Cox regression models. A total of 641 incident VTE cases accrued over a median follow-up of 16 yrs. Participants in the highest quintile of leg length were at 59% (95% CI: 22%-108%) greater risk of VTE, relative to the lowest quintile. For height, risk was 45% (12%-88%) greater for those in the highest quintile, compared to the lowest. When leg length and height were modeled simultaneously leg length remained associated with VTE risk (HR per 1 SD: 1.21 (1.04-1.40) while height was unrelated (HR per 1 SD: 1.00 (0.86-1.16). To conclude, participants with longer legs were at greater risk of incident VTE, and leg length explained the relation of height to VTE. It remains to be established whether this finding is due to greater venous surface area, a larger number of venous valves, or greater hydrostatic pressure among individuals with longer legs.
height; leg length; venous thromboembolism; Atherosclerosis Risk in Communities Study (ARIC); Cardiovascular Health Study (CHS)
This study examined whether carotid artery intimal-medial thickness (cIMT) is associated with genetic variations (SNPs) in a hemodynamics-responsive gene pathway.
Subjects were Cardiovascular Health Study participants free of cardiovascular events at baseline (N=3388). Genotype was measured using Illumina 370CNV HumanHap chip. Carotid IMT was measured using ultrasound. Estimated mean differences in cIMT per additional minor allele for 366 SNPs in MAP2K5, MAPK7, MEF2A/C, and KLF2 were adjusted for sex, age, clinic, and medication use. SNP-SNP interactions were examined using logic regression for 71 tagSNPs.
None of the associations was significant after correction for multiple comparisons; smallest P-value=0.065 for MAP2K5 and common cIMT. The best-performing logic regression tree combined two SNPs in MAP2K5—rs745212 and rs12905175— and common cIMT; this association was not significant, corrected P-value=0.062.
There was not strong evidence of association between genetic variants in a hemodynamics-responsive gene pathway and atherosclerosis among older adults.
Cardiovascular Health Study (CHS); candidate gene study; carotid intima-media thickness (cIMT); hemodynamics response; fluid shear stress; endothelium / endothelial cells; Kruppel-like factor 2 (KLF2); Mitogen-activated protein kinase 7 (MAPK7); Myocyte-specific enhancer factor 2 A/C (MEF2A/C); Mitogen-activated protein kinase kinase 5 (MAP2K5)
The withdrawal of cerivastatin involved an uncommon but serious adverse reaction, rhabdomyolysis. The bimodal response--rhabdomyolysis in a small proportion of users-- points to genetic factors as a potential cause. We conducted a case-control study to evaluate genetic markers for cerivastatin-associated rhabdomyolysis.
The study had two components: a candidate gene study to evaluate variants in CYP2C8, UGT1A1, UGT1A3, and SLCO1B1; and a genome-wide association (GWA) study to identify risk factors in other regions of the genome. 185 rhabdomyolysis cases were frequency matched to statin-using controls from the Cardiovascular Health Study (n=374) and the Heart and Vascular Health Study (n=358). Validation relied on functional studies.
Permutation test results suggested an association between cerivastatin-associated rhabdomyolysis and variants in SLCO1B1 (p = 0.002), but not variants in CYP2C8 (p = 0.073) or the UGTs (p = 0.523). An additional copy of the minor allele of SLCO1B1 rs4149056 (p.Val174Ala) was associated with the risk of rhabdomyolysis (OR: 1.89, 95% CI: 1.40 to 2.56). In transfected cells, this variant reduced cerivastatin transport by 40% compared with the reference transporter (p < 0.001). The GWA identified an intronic variant (rs2819742) in the ryanodine receptor 2 gene (RYR2) as significant (p=1.74E-07). An additional copy of the minor allele of the RYR2 variant was associated with a reduced risk of rhabdomyolysis (OR: 0.48; 95% CI: 0.36 to 0.63).
We identified modest genetic risk factors for an extreme response to cerivastatin. Disabling genetic variants in the candidate genes were not responsible for the bimodal response to cerivastatin.
Genetics; drugs; epidemiology; rhabdomyolysis
Automated pharmacy databases are increasingly available for assessing medication use, but research on the validity of these data is incomplete. This study aimed to measure agreement on warfarin and aspirin use between medical records and automated pharmacy data among patients with newly detected atrial fibrillation (AF).
Patients with newly detected AF (n = 1953) were previously identified in a cohort study at Group Health (GH) in Washington State. Medical records were reviewed for information on risk factors and medication use, as well as clinical care during the 6 months after AF onset. Medication data were also obtained from the GH pharmacy database. We determined the sensitivity, specificity, and positive predictive value (PPV) as measures of the validity of the GH pharmacy database as compared with medical records for warfarin and aspirin use during the first 6 and 3 months after AF onset. We also calculated the κ statistic.
For warfarin use, in comparison with the medical record review, the sensitivity, specificity, and PPV for the GH pharmacy database were excellent, and agreement was almost perfect in the 3- and 6-month periods after AF onset (κ = 0.92 and 0.93, respectively). For aspirin use, the GH pharmacy database had low sensitivity but high specificity, and agreement was only fair for these two periods (κ = 0.28 and 0.31, respectively).
The GH pharmacy database is a valuable source of data for pharmacoepidemiologic research on warfarin use among patients with AF. However, the database cannot be recommended for assessment of aspirin use.
warfarin; medical records; pharmacy database; pharmacoepidemiology; validity; agreement
Biomarkers of inflammation and hemostasis have been associated with left ventricular (LV) mass. We studied relationships of C-reactive protein (CRP), interleukin-6 (IL6), D-dimer, soluble intercellular adhesion molecule-1 (sICAM-1), plasminogen activator inhibitor 1 (PAI-1), soluble thrombomodulin (sTM), soluble tumor necrosis factor type 1 receptor (sTNFR1), von Willebrand factor (vWF), soluble E-selectin (sE-selectin), factor VIII, fibrinogen, matrix metalloproteinase 3 (MMP3), and matrix metalloproteinase 9 (MMP9) with LV mass in an asymptomatic population. Multi-Ethnic Study of Atherosclerosis participants underwent magnetic resonance imaging to characterize LV mass; biomarkers were measured using standardized protocols (N = 763 to 4979). Adjusted models were used to associate each biomarker with LV mass while correcting for potential confounding.
LV mass was associated with many biomarkers after adjustment for demographic characteristics and traditional cardiovascular risk factors. Although the demographic and risk factor adjustments attenuated the association of CRP and IL6 with LV mass, further adjustment for weight changed regression coefficients from positive to negative for CRP and IL6 for LV mass. sTM, Factor VIII, and vWF were directly associated with LV mass in fully-adjusted models. For sTNFR1, sICAM-1, D-dimer, fibrinogen, and PAI-1, adjustment for risk factors and weight rendered associations with LV mass nonsignificant.
In this large cohort free of clinical cardiovascular disease, several hemostasis and inflammation markers were associated with LV mass. The unusual finding of a negative relationship of CRP and IL6 with LV mass only after adjustment for weight suggests that the effects of inflammation on LV mass are strongly influenced by obesity.
Left ventricle; biomarker; hemostasis; inflammation
Background. The incidence of venous thromboembolism (VTE) is increased with severe kidney disease, but whether less-severe chronic kidney disease (CKD) increases the risk of VTE is less certain.
Methods. We studied this in a prospective cohort of 10 700 whites and African Americans, aged 53–75 years, attending Visit 4 (1996–98) of the Atherosclerosis Risk in Communities Study. Estimated glomerular filtration rate (eGFR) values were estimated from prediction equations based on serum creatinine (eGFRcreat) or cystatin C (eGFRcys). Normal kidney function was defined as eGFR ≥90 ml/min/1.73 m2, mildly decreased kidney function as eGFR between 60 and 89 ml/min/1.73 m2 and Stage 3 to 4 CKD as eGFR between 15 and 59 ml/min/1.73 m2. VTE occurrence (n = 228) was ascertained over a median of 8.3 years.
Results. For eGFRcys, the age-, race- and sex-adjusted hazard ratios of total VTE were 1.0, 1.40 and 1.94 (P trend = 0.003) for normal kidney function, mildly impaired kidney function and Stage 3 to 4 CKD, respectively. These respective hazard ratios were moderately attenuated to 1.0, 1.26 and 1.60 (P trend = 0.04) with adjustment for hormone replacement therapy, diabetes and body mass index. Associations between CKD based on eGFRcys and VTE were slightly stronger for idiopathic VTE than for secondary VTE. In contrast, CKD based on eGFRcreat was not associated with total VTE occurrence.
Conclusions. Stage 3 to 4 CKD, based on eGFRcys but not eGFRcreat, was associated with an approximately 1.6-fold increased risk of VTE.
chronic kidney disease; prospective study; pulmonary embolism; venous thromboembolism
Cerivastatin, an HMG-CoA reductase inhibitor withdrawn from the market due to serious adverse effects, is metabolized primarily by CYP2C8. The occurrence of associated myotoxicity and rhabdomyolysis were attributed to altered cerivastatin pharmacokinetics due to gemfibrozil-inhibition or genetic variations in CYP2C8 and drug transporters involved in cerivastatin clearance. However, the effect of CYP2C8 genetic variation on cerivastatin metabolism has not been fully elucidated. In this study, patients (n=126) with confirmed cases of rhabdomyolysis following cerivastatin administration had their CYP2C8 gene resequenced and the metabolism of cerivastatin by the discovered CYP2C8 variants was investigated. In this unique patient population, twelve novel SNPs were discovered of which six were exclusively found in patients not using gemfibrozil. Three rare exonic variants resulted in amino acid substitutions and a frame shift deletion (V472fsL494 generating a defective mostly heme-free CYP2C8 protein). A particular promotor located deletion (-635_-634delTA) was tightly linked to CYP2C8*3. Seven exonic variants were heterologously expressed in E.coli to assess their influence on cerivastatin metabolism. Recombinant CYP2C8.3 and CYP2C8.4 displayed an increase in cerivastatin metabolic clearance up to six fold compared to the wild type enzyme. Similarly, an independent sample of microsomes from human livers carrying the CYP2C8*3 and CYP2C8*4 alleles exhibited a 2 to 14-fold increase in normalized cerivastatin intrinsic clearance, compared to microsomes from livers carrying only the wild type allele. This gain or loss of catalytic function could certainly alter cerivastatin pharmacokinetics and may influence, at least in part, susceptibility to the development of myotoxicity.
pharmacogenetics; CYP2C8 variants; CYP2C8*4; CYP2C8*3; promotor linkage disequilibrium; non-functional variants
Diabetes may be an independent risk factor for atrial fibrillation. However, results from prior studies are in conflict, and no study has examined diabetes duration or glycemic control.
To examine the association of diabetes with risk of atrial fibrillation and to describe risk according to diabetes duration and glycemic control.
A population-based case-control study.
Within a large, integrated healthcare delivery system, we identified 1,410 people with newly-recognized atrial fibrillation from ICD-9 codes and validated cases by review of medical records. 2,203 controls without atrial fibrillation were selected from enrollment lists, stratified on age, sex, hypertension, and calendar year.
Information on atrial fibrillation, diabetes and other characteristics came from medical records. Diabetes was defined based on physician diagnoses recorded in the medical record, and pharmacologically treated diabetes was defined as receiving antihyperglycemic medications. Information about hemoglobin A1c levels came from computerized laboratory data.
Among people with atrial fibrillation, 252/1410 (17.9%) had pharmacologically treated diabetes compared to 311/2203 (14.1%) of controls. The adjusted OR for atrial fibrillation was 1.40 (95% CI 1.15-1.71) for people with treated diabetes compared to those without diabetes. Among those with treated diabetes, the risk of developing atrial fibrillation was 3% higher for each additional year of diabetes duration (95% CI 1-6%). Compared to people without diabetes, the adjusted OR for people with treated diabetes with average hemoglobin A1c ≤7 was 1.06 (95% CI 0.74-1.51); for A1c >7 but ≤8, 1.48 (1.09-2.01); for A1c >8 but ≤9, 1.46 (1.02-2.08); and for A1c >9, 1.96 (1.22–3.14).
Diabetes was associated with higher risk of developing atrial fibrillation, and risk was higher with longer duration of treated diabetes and worse glycemic control. Future research should identify and test approaches to reduce the risk of atrial fibrillation in people with diabetes.
arrhythmia; atrial fibrillation; diabetes mellitus; glycemic control; diabetes complications
To test whether depression is associated with an increased risk of incident diabetic foot ulcers.
The Pathways Epidemiologic Study is a population-based prospective cohort study of 4839 patients with diabetes in 2000–2007. The present analysis included 3474 adults with type 2 diabetes and no prior diabetic foot ulcers or amputations. Mean follow-up was 4.1 years. Major and minor depression assessed by the Patient Health Questionnaire-9 (PHQ-9) were the exposures of interest. The outcome of interest was incident diabetic foot ulcers. We computed the hazard ratio (HR) and 95% CI for incident diabetic foot ulcers, comparing patients with major and minor depression to those without depression and adjusting for sociodemographic characteristics, medical comorbidity, glycosylated hemoglobin (HbA1c), diabetes duration, insulin use, number of diabetes complications, body mass index, smoking status, and foot self-care. Sensitivity analyses also adjusted for peripheral neuropathy and peripheral arterial disease as defined by diagnosis codes.
Compared to patients without depression, patients with major depression by PHQ-9 had a two-fold increase in the risk of incident diabetic foot ulcers (adjusted HR 2.00, 95% CI: 1.24, 3.25). There was no statistically significant association between minor depression by PHQ-9 and incident diabetic foot ulcers (adjusted HR 1.37, 95% CI: 0.77, 2.44).
Major depression by PHQ-9 is associated with a two-fold higher risk of incident diabetic foot ulcers. Future studies of this association should include better measures of peripheral neuropathy and peripheral arterial disease, which are possible confounders and/or mediators.
diabetes; depression; foot ulcers; complications
The incidence of venous thromboembolism (VTE) is increased in patients with albuminuria. However, whether a low serum albumin concentration is associated with increased risk of VTE has been a matter of controversy. We determined the association of serum albumin with VTE incidence in two large, prospective, population-based cohorts: the Atherosclerosis Risk in Communities (ARIC) Study (n = 15,300) and the Cardiovascular Health Study (CHS) (n = 5,400). Validated VTE occurrence (n=462 in ARIC and n=174 in CHS) was ascertained during follow-up. In both studies, after adjustment for age, sex, race, use of hormone replacement therapy, estimated GFR, history of cancer, and diabetes, serum albumin tended to be associated inversely with VTE. The adjusted hazard ratio per standard deviation lower albumin was 1.18 (95% CI = 1.08, 1.31) in ARIC and 1.10 (95% CI = 0.94, 1.29) in CHS. The hazard ratio for albumin below (versus above) the fifth percentile was 1.28 (95% CI = 0.90, 1.84) in ARIC and 1.80 (95% CI = 1.11, 2.93) in CHS. In conclusion, low serum albumin was a modest marker of increased VTE risk. The observed association likely does not reflect cause and effect, but rather that low serum albumin reflects a hyperinflammatory or hypercoagulable state. Whether this association has clinical relevance warrants further study.
albumin; prospective study; pulmonary embolism; venous thrombosis
Little information is available about the association of depression with long-term control of glycemia, blood pressure, or lipid levels in patients with diabetes.
To determine whether minor and major depression at study enrollment compared with no depression are associated with higher average HbA1c, systolic blood pressure (SBP) and LDL cholesterol over the long term in patients with an indication for or receiving drug treatment.
A total of 3,762 patients with type 2 diabetes mellitus enrolled in the Pathways Epidemiologic Study in 2001–2002 and followed for 5 years.
Depression was assessed at study enrollment using the Patient Health Questionnaire-9 (PHQ-9). SBP and information on cardiovascular co-morbidity were abstracted from medical records, and LDL cholesterol and HbA1c measured during clinical care were obtained from computerized laboratory data during a median of 4.8 years’ follow-up.
Among those with an indication for or receiving drug treatment, after adjustment for demographic and clinical characteristics, average long-term HbA1c, SBP, and LDL cholesterol did not differ in patients with comorbid diabetes and minor or major depression compared with those with diabetes alone.
The adverse effect of depression on outcomes in patients with diabetes may not be mediated in large part by poorer glycemic, blood pressure, or lipid control. Further study is needed of the biologic effects of depression on patients with diabetes and their relation to adverse outcomes.
depression; diabetes; glycemia; hypertension; hyperlipidemia
In a prospective study of primary care patients with diabetes we determined whether macrovascular or microvascular events or coronary, cerebrovascular or peripheral vascular procedures during follow-up were associated with meeting criteria for major depression at 5-year follow-up.
Design, Patients and Measurements
A total of 2759 patients with diabetes mellitus were followed over a 5-year period. Evidence of macrovascular and microvascular events and coronary, cerebrovascular and peripheral vascular procedures was assembled from automated data using ICD-9 and CPT codes and was verified by chart review. Depression was measured using the Patient Health Questionnaire.
After controlling for baseline severity of depression symptoms and history of depression, having 1 or more coronary procedures during follow-up, and baseline severity of diabetes symptoms were strong predictors of having major depression at 5-year follow-up.
The risk of major depression among persons with diabetes is increased by prior depression history, baseline diabetes symptoms, and cardiovascular procedures.
Both depression and diabetes have been found to be risk factors for dementia. This study examined whether comorbid depression in patients with diabetes increases the risk for dementia compared to those with diabetes alone.
We conducted a prospective cohort study of 3,837 primary care patients with diabetes (mean age 63.2 ± 13.2 years) enrolled in an HMO in Washington State. The Patient Health Questionnaire (PHQ-9) was used to assess depression at baseline, and ICD-9 diagnoses for dementia were used to identify cases of dementia. Cohort members with no previous ICD-9 diagnosis of dementia prior to baseline were followed for a 5-year period. The risk of dementia for patients with both major depression and diabetes at baseline relative to patients with diabetes alone was estimated using cause-specific Cox proportional hazard regression models that adjusted for age, gender, education, race/ethnicity, diabetes duration, treatment with insulin, diabetes complications, nondiabetes-related medical comorbidity, hypertension, BMI, physical inactivity, smoking, HbA1c, and number of primary care visits per month.
Over the 5-year period, 36 of 455 (7.9%) patients with major depression and diabetes (incidence rate of 21.5 per 1,000 person-years) versus 163 of 3,382 (4.8%) patients with diabetes alone (incidence rate of 11.8 per 1,000 person-years) had one or more ICD-9 diagnoses of dementia. Patients with comorbid major depression had an increased risk of dementia (fully adjusted hazard ratio 2.69, 95% CI 1.77, 4.07).
Patients with major depression and diabetes had an increased risk of development of dementia compared to those with diabetes alone. These data add to recent findings showing that depression was associated with an increased risk of macrovascular and microvascular complications in patients with diabetes.
depression; dementia; diabetes
Numerous studies have established that hormone replacement therapy increases the risk of venous thromboembolism (VTE), but an association of endogenous estrogen exposure with the incidence of VTE is not fully established. Using a prospective design combining the Atherosclerosis Risk in Communities and the Cardiovascular Health Study cohort, we studied the 12-year risk of VTE in relation to hormone replacement therapy use, age at menopause, parity number, and type of menopause in 8,236 post-menopausal women. There were no significant associations of age at menopause, parity number, or type of menopause with incidence of VTE. Women currently using hormone replacement had a 1.6-times higher multivariate-adjusted rate ratio (RR) of VTE compared with those without hormone use in the time-dependent model (RR=1.60, 95% CI, 1.06-2.36; Population attributable fraction=6.7%, 95%CI, 1.0-10.3). When we excluded women with 1-year or more duration of hormone therapy at baseline, the associations was stronger (RR=2.02, 95%CI, 1.31-3.12). The multivariate-adjusted RRs of VTE for current users tended to be higher in those with idiopathic VTE (RR=2.40, 95%CI, 1.40-4.12) than those with secondary VTE (RR=1.08, 95%CI, 0.63-1.85). Hormone replacement therapy is associated with increased risk of VTE, but reproductive history markers of endogenous estrogen exposure were not associated with VTE.
Epidemiology; Hormone therapy; Menopause; Risk factors; Venous thrombosis
We assessed the association of genetic variation in MMP3 and MMP9 with risk of myocardial infarction and stroke.
A case-control study was conducted among members of Group Health (GH), a large integrated health care delivery system. Case subjects with incident non-fatal myocardial infarction (n = 854), ischemic stroke (n = 367), and hemorrhagic stroke (n = 66) were identified and validated. A matched control group was selected from among GH members without myocardial infarction or stroke (n=2696). Haplotype-tagging sets of single nucleotide polymorphisms (SNPs) in MMP3 and MMP9 were genotyped.
MMP3 haplotype 2 was associated with reduced risk of myocardial infarction (adjusted odds ratio [OR] per copy = 0.80, 95% confidence interval 0.66, 0.98) and increased risk of hemorrhagic stroke (OR = 1.69, 95% confidence interval 1.05, 2.75). Results for MMP3 haplotype 2 and ischemic stroke resembled those for myocardial infarction but did not achieve statistical significance (OR = 0.85, 95% confidence interval 0.64, 1.12). No individual SNP identified MMP3 haplotype 2, and none of the individual MMP3 SNPs were associated with myocardial infarction or stroke. MMP9 haplotypes or SNPs were not associated with myocardial infarction or stroke.
MMP3 haplotype may predict both cardiac events and stroke.
Myocardial infarction; stroke; genetics
Methods to index left ventricular (LV) mass, measured by cardiovascular magnetic resonance (CMR), for body size have not been investigated. The purposes of this study were to develop allometric indices for LV mass measured by CMR and compare estimates of the prevalence and predictive value of LV hypertrophy defined by a new allometric height-weight index, LV mass/body surface area (BSA), height indices (a new allometric height index; and previously derived indices from echocardiographic measurements: LV mass/height2, LV mass/height2.7), and non-indexed LV mass. 5,004 participants from the Multi-Ethnic Study of Atherosclerosis (MESA) with CMR measurements of LV mass and no clinical cardiovascular disease at baseline were followed for a median of 4.1 years. The new indices and limits for hypertrophy (95th percentile) were derived from 822 normal-weight, normotensive, non-diabetic MESA participants. 107 events (coronary heart disease or stroke) were observed. The estimated prevalence of hypertrophy at baseline and hazard ratio for event associated with hypertrophy were 8% and 2.4 with the new allometric height-weight index, 11% and 2.2 with LV mass/BSA, 23–24% and 2.0–2.1 with height indices, and 20% and 1.7 with non-indexed LV mass. A statistically significant difference was detected between the hazard ratios based on the new height-weight index and non-indexed LV mass. The prevalence of hypertrophy is higher for indices that do not account for weight. The predictive value of hypertrophy is significantly better with the new allometric height-weight index than with non-indexed LV mass and may be better than indices without weight.
Cardiovascular risk; Hypertension; Hypertrophy; LV mass index; Magnetic resonance imaging; Obesity
To prospectively examine the association of depression with risks for advanced macrovascular and microvascular complications among patients with type 2 diabetes.
RESEARCH DESIGN AND METHODS
A longitudinal cohort of 4,623 primary care patients with type 2 diabetes was enrolled in 2000–2002 and followed through 2005–2007. Advanced microvascular complications included blindness, end-stage renal disease, amputations, and renal failure deaths. Advanced macrovascular complications included myocardial infarction, stroke, cardiovascular procedures, and deaths. Medical record review, ICD-9 diagnostic and procedural codes, and death certificate data were used to ascertain outcomes in the 5-year follow-up. Proportional hazard models analyzed the association between baseline depression and risks of adverse outcomes.
After adjustment for prior complications and demographic, clinical, and diabetes self-care variables, major depression was associated with significantly higher risks of adverse microvascular outcomes (hazard ratio 1.36 [95% CI 1.05–1.75]) and adverse macrovascular outcomes (1.24 [1.0–1.54]).
Among people with type 2 diabetes, major depression is associated with an increased risk of clinically significant microvascular and macrovascular complications over the ensuing 5 years, even after adjusting for diabetes severity and self-care activities. Clinical and public health significance of these findings rises as the incidence of type 2 diabetes soars. Further research is needed to clarify the underlying mechanisms for this association and to test interventions to reduce the risk of diabetes complications among patients with comorbid depression.
Background and purpose
The relative risk of ischemic stroke associated with transient ischemic attack (TIA) is not well-defined because most studies of stroke after TIA did not include comparison groups. We sought to estimate short term and long term relative risks of ischemic stroke associated with clinically diagnosed TIA.
We used data from a population-based case-control study. Cases were hypertensive men and women, and postmenopausal women, ages 30–79, with incident ischemic stroke. Controls were sampled within strata of age, sex, hypertension status, and calendar year. The index date was the stroke date for cases and a random date for controls. Clinically diagnosed TIA was ascertained from medical records. We used logistic regression to calculate odds ratios (ORs).
The study included 1,914 stroke cases and 9,874 controls. Clinically diagnosed TIA was present in 215 (11.2%) cases and 252 (2.5%) controls. Analyses focused on the most recent TIA before index date. For TIA <1 month before index date, the adjusted OR for stroke was 30.4 (95% CI: 10.4, 89.4); for TIA 1–3 months before index date, it was 18.9 (8.58, 41.6); for TIA 4–6 months before index date, it was 3.16 (1.27, 7.82); and for TIA more than five years before index date, it was 1.87 (1.22, 2.85).
The relative risk of ischemic stroke was high for TIA diagnosed within the past three months, and moderately high for TIA diagnosed more than five years in the past, compared with no history of clinically diagnosed TIA.
stroke; transient ischemic attack; epidemiology; case-control study
Little is known about how change in depressive symptoms over time is associated with change in weight.
Longitudinal associations between change in depression (Patient Health Questionnaire-9 [PHQ-9]) and weight (self-reported and chart abstracted) were examined in 2,600 patients with type 2 diabetes (mean age 62, SD = 11.6) who were surveyed by telephone in 2001–2002 and 5 years later as part of the Pathways study. Mixed effects regression analyses compared a) patients with persistently low depression symptoms with those whose depression worsened (increased at least 5 points on PHQ-9) over 5 years and b) patients with persistently high depression symptoms with those who improved (decreased at least 5 points on PHQ-9) over 5 years.
Those who worsened in comparison to those with persistently low depression symptoms did not differ in their pattern of weight change (z = 1.54, p = .12). Both groups weighed approximately 92 kg at baseline and lost approximately 2 kg. A significantly different pattern of change over time was observed for those with persistently high depression symptoms in comparison to those whose depression improved (z = 1.98, p = .04). Although the groups had almost identical weight at baseline (approximately 100 kg), at the 5-year assessment, those with persistently high depression symptoms had about half the weight loss (M = −1.71, SD = 9.08) in comparison to those whose depression improved (M = −3.62, SD = 19.93).
In persons with diabetes who have clinically significant levels of depressive symptoms, improvement in depression is accompanied by significantly greater, clinically significant weight loss.
Depression; Obesity; Diabetes