Guidelines recommend evaluation of cardiac function, valvular and ischemic heart disease, and thyroid, kidney, and liver function upon initial diagnosis of atrial fibrillation (AF).
We hypothesized that initial workup of patients with newly identified AF would vary by age, sex, and burden of comorbid illness.
In a retrospective analysis of a large sample of commercially insured patients 18 to 64 years (n=40,245) and a nationally representative 5% cohort of Medicare beneficiaries 65 years or older (n=204,676), we measured claims for guideline-recommended services for initial evaluation of AF among patients with a new diagnosis between 2000 and 2008.
From 30 days before through 90 days after AF diagnosis, basic evaluation, including physician visit, electrocardiogram, and echocardiography, was completed in up to 66.6% of patients. Completion rates for all guideline-recommended evaluations were 17.4% in the commercially insured sample and 18.5% in the Medicare cohort in 2007. Evaluation rates increased over time. Blood tests assessing thyroid function were documented for approximately one-third of patients in each cohort. Increasing the observation period to 1 year before through 3 months after the AF diagnosis markedly increased completion rates, but rates of thyroid function testing remained low (50% to 60%). There were minor differences in evaluation completeness by sex, race, and geographic region.
Differences in guideline-recommended evaluation rates by demographic characteristics after a new diagnosis of AF were of minor clinical importance. Basic evaluation had satisfactory completion rates; however, rates of laboratory testing were low.
Arrhythmia; Diagnosis; Electrophysiology; Outcome Assessment (Health Care)
Apart from obesity, it remains controversial whether atherosclerosis and its cardiovascular risk disease (CVD) factors are associated with risk of venous thromboembolism (VTE). Using data from the Atherosclerosis Risk in Communities study (ARIC), we evaluated associations between CVD risk factors and incident VTE in a cohort of 15,340 participants who were free a history of VTE and/or anticoagulant use on enrolment. The CVD risk factors were updated during the follow-up period. Over a mean follow-up time of 15.5 years (237,375 person-years), 468 participants had VTE events. Adjusting for demographic variables and body mass index (BMI), current smokers were at greater risk [HR of 1.44 (95% CI: 1.12–1.86)] compared to non-smokers. There was a positive monotonic association between BMI and VTE risk. Individuals with a BMI ≥35 kg/m2 had a HR for VTE of 3.09 (95%CI: 2.26–4.23) compared to those with normal BMI (<25 kg/m2). Greater physical activity was associated with lower VTE risk in a demographic adjusted model; however, this association became non-significant following adjustment for BMI. Alcohol intake, diabetes, hypertension, high-density lipoprotein and low-density lipoprotein cholesterol, and triglycerides were not associated with VTE risk. In conclusion, among the well-established CVD risk factors, only current smoking and obesity were independently associated with VTE risk in this large cohort where risk factors were updated serially during follow-up. This finding corroborates that the pathogenesis of venous disease differs from that of atherosclerotic disease.
Deep-vein thrombosis; pulmonary embolism; risk factors
Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia in clinical practice, affecting approximately 2.3 million people in the USA and 4.5 million people in the European Union. It is unclear whether plasma free fatty acids (FFA) influence the risk of AF among older adults. The aim of this study was to prospectively examine the association between plasma FFA and incident AF in a prospective cohort of 4,175 men and women aged ≥65 years from the Cardiovascular Health Study. Plasma concentrations of FFA were measured in duplicate during the 1992-93 examination. Incident AF was ascertained based on study EKG and hospitalization records during follow up. We used Cox regression to estimate relative risks of AF. The average age at baseline was 74.6 ± 5.1 years. During a mean follow up of 10.0 years, 1,041 new cases of AF occurred. Crude incidence rates of AF were 23.7, 23.3, 23.9, and 29.7 cases/1,000 person-years across consecutive quartiles of plasma FFA. There was a positive association between plasma FFA and the risk of AF. Multivariable adjusted hazard ratios (95% CI) for incident AF were 1.00 (ref), 1.02 (0.85-1.21), 1.05 (0.88-1.26), and 1.29 (1.08-1.55) from lowest to the highest quartile of FFA, respectively. In a secondary analysis restricted to the first five years of follow up, this association persisted. In conclusion, our data show an elevated risk of AF with higher plasma FFA among community dwelling older adults.
Free Fatty Acids; Atrial Fibrillation; Risk Factors; Epidemiology
To characterize the validity of algorithms to identify AF from electronic health data through a systematic review of the literature, and to identify gaps needing further research.
Two reviewers examined publications during 1997–2008 that identified patients with AF from electronic health data and provided validation information. We abstracted information including algorithm sensitivity, specificity, and positive predictive value (PPV).
We reviewed 544 abstracts and 281 full-text articles, of which 18 provided validation information from 16 unique studies. Most used data from before 2000, and 10 of 16 used only inpatient data. Three studies incorporated electronic ECG data for case identification or validation. A large proportion of prevalent AF cases identified by ICD-9 code 427.31 were valid (PPV 70–96%, median 89%). Seven studies reported algorithm sensitivity (range, 57–95%; median 79%). One study validated an algorithm for incident AF and reported a PPV of 77%.
The ICD-9 code 427.31 performed relatively well, but conclusions about algorithm validity are hindered by few recent data, use of nonrepresentative populations, and a disproportionate focus on inpatient data. An optimal contemporary algorithm would likely draw on inpatient and outpatient codes and electronic ECG data. Additional research is needed in representative, contemporary populations regarding algorithms that identify incident AF and incorporate electronic ECG data.
atrial fibrillation; cardiac arrhythmia; epidemiology; validation; positive predictive value; sensitivity
This study aimed to test whether aortic valve calcium (AVC) is independently associated with coronary and cardiovascular events in a primary-prevention population.
Aortic sclerosis is associated with increased cardiovascular morbidity and mortality among the elderly, but the mechanisms underlying this association remain controversial and it is unknown if this association extends to younger individuals.
We performed a prospective analysis of 6,685 participants in the Multi-Ethnic Study of Atherosclerosis. All subjects, aged 45-84 years and free of clinical cardiovascular disease at baseline, underwent computed tomography for AVC and coronary artery calcium (CAC) scoring. The primary, pre-specified combined endpoint of cardiovascular events included myocardial infarctions, fatal and non-fatal strokes, resuscitated cardiac arrest and cardiovascular death, while a secondary combined endpoint of coronary events excluded strokes. The association between AVC and clinical events was assessed using Cox proportional hazards regression with incremental adjustments for demographics, cardiovascular risk factors, inflammatory biomarkers and subclinical coronary atherosclerosis.
Over a median follow up of 5.8 [IQR 5.6, 5.9] years, adjusting for demographics and cardiovascular risk factors, subjects with AVC (n=894, 13.4%) had higher risks of cardiovascular (HR, 1.50; 95% CI, 1.10-2.03) and coronary (HR, 1.72; 95% CI, 1.19-2.49) events compared to those without AVC. Adjustments for inflammatory biomarkers did not alter these associations, but adjustment for CAC substantially attenuated both cardiovascular (HR, 1.32; 95% CI: 0.98-1.78) and coronary (HR, 1.41; 95% CI, 0.98-2.02) event risk. AVC remained predictive of cardiovascular mortality even after full adjustment (HR, 2.51; 95% CI, 1.22-5.21).
In this multiethnic MESA cohort, free of clinical cardiovascular disease, AVC predicts cardiovascular and coronary event risk independent of traditional risk factors and inflammatory biomarkers, likely due to the strong correlation between AVC and subclinical atherosclerosis. The association of AVC with excess cardiovascular mortality beyond coronary atherosclerosis risk merits further investigation.
Older women have a higher prevalence of systolic hypertension than do men; however, whether or not this relates to arterial properties, such as distensibility coefficient (DC), is not known. We examined whether the association of carotid artery DC with age differed by sex in the Multi-Ethnic Study of Atherosclerosis (MESA).
B-mode ultrasound-measured carotid diameters and brachial pressures were obtained from 6359 participants (53% female, 38% white, 12% Chinese, 27% black, 22% Hispanic, aged 45–85 years) of the MESA baseline examination. The within-individual slopes of 2log(diameter) vs. blood pressure fit using mixed models (MM) are interpreted as the DC, and interaction terms are interpreted as differences in DC. The MM calculation allows for correction of the confounding caused by the association of age, sex, and race with blood pressure, the denominator in the calculation of DC.
DC was associated with age, sex, and race (all p<0.001). Women had a greater age-related lowering of DC compared to men (2.52×10−5 vs. 2.16×10−5/mm Hg lower DC per year of age, p=0.006). Mean diameter of carotid arteries was greater with age (p<0.001); this association also was significantly stronger in women compared to men (0.24% vs. 0.14% larger mean carotid diameter per year of age, p<0.001).
Greater stiffening and enlargement of arteries are seen in older women compared to older men. This implies that the afterload on the heart of older women is likely to be greater than that among older men.
Atrial fibrillation (AF) is the most common sustained arrhythmia in the elderly, and shares several risk factors with diastolic dysfunction, including hypertension and advanced age. The purpose of this study is to examine diastolic dysfunction as a risk for incident AF.
Methods and results
We examined the association of echocardiographic parameters of diastolic function with the incidence of AF in 4480 participants enrolled in the Cardiovascular Health Study, an ongoing cohort of community-dwelling older adults from four US communities. Participants underwent baseline echocardiography in 1989–1990 and were followed for incident AF on routine follow-up and hospitalizations. After 50 941 person-years of follow-up (median follow-up time 12.1 years), 1219 participants developed AF. In multivariable-adjusted age-stratified Cox models, diastolic echocardiographic parameters were significantly associated with the risk of incident AF. The most significant parameters were the Doppler peak E-wave velocity and left atrial diameter, which demonstrated a positive nonlinear association [HR 1.5 (CI 1.3–1.9) and HR 1.7 (CI 1.4–2.1) for highest vs. lowest quintile, respectively], and Doppler A-wave velocity time integral, which displayed a U-shaped relationship with the risk of AF [HR 0.7 (CI 0.6–0.9) for middle vs. lowest quintile]. Each diastolic parameter displayed a significant association with adjusted NT-proBNP levels, although the nature of the association did not entirely parallel the risk of AF. Further cluster analysis revealed unique patterns of diastolic function that may identify patients at risk for AF.
In a community-based population of older adults, echocardiographic measures of diastolic function are significantly associated with an increased risk of AF.
Atrial fibrillation; Diastolic dysfunction; Ageing; Echocardiography
Rationale: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.
Objectives: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.
Methods: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV1 and its ratio to FVC (FEV1/FVC) both less than their respective lower limits of normal as determined by published reference equations.
Measurements and Main Results: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV1/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.
Conclusions: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.
chronic obstructive pulmonary disease; single-nucleotide polymorphism; genes
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
Few studies have examined the relationship of α‐linolenic acid (ALA 18:3n‐3), an intermediate‐chain essential n‐3 polyunsaturated fatty acid derived from plants and vegetable oils, with incident atrial fibrillation (AF).
Methods and Results
The study population included participants from the Cardiovascular Health Study, a community‐based longitudinal cohort of adults aged 65 or older, free of prevalent coronary heart disease and atrial fibrillation. We assessed the associations of plasma phospholipid and dietary ALA with incident AF using Cox regression. The biomarker analysis comprised a total of 2899 participants, and the dietary analysis comprised 4337 participants. We found no association of plasma phospholipid ALA and incident AF. Comparing each of the second, third, and fourth quartiles to the lowest quartile, the hazard ratios for AF were 1.11 (95% CI, 0.90 to 1.37), 1.09 (95% CI, 0.88 to 1.35), and 0.92 (95% CI, 0.74 to 1.15), after adjustment for age, sex, race, clinic, education, smoking, alcohol, body mass index, waist circumference, diabetes, heart failure, stroke, treated hypertension, and physical activity (P trend=0.48). When dietary ALA was considered the exposure of interest, results were similar.
Results from this prospective cohort study of older adults indicate no association of plasma phospholipid or dietary ALA and incident AF.
atrial fibrillation; epidemiology; fatty acids; nutrition
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