Do cardiovascular risk factors confer the same risk for cardiovascular outcomes in rheumatoid arthritis patients as in non-rheumatoid arthritis patients?

OBJECTIVE: To compare the frequency of traditional cardiovascular (CV) risk factors in rheumatoid arthritis (RA) compared to non-RA subjects, and examine their impact on the risk of developing selected CV events (myocardial infarction (MI), heart failure (HF) and CV death) in these two groups. METHODS: We examined a population-based incidence cohort of subjects with RA (defined according to the 1987 American College of Rheumatology criteria), and an age- and sex-matched non-RA cohort. All subjects were followed longitudinally through their complete community medical records, until death, migration, or 1 January 2001. Clinical CV risk factors and outcomes were defined using validated criteria. The chi2 test was used to compare the frequency of each CV risk factor at baseline. Person-years methods were used to estimate the rate of occurrence of each CV risk factor during follow-up. Cox models were used to examine the influence of CV risk factors on the development of CV outcomes. RESULTS: A total of 603 RA and 603 non-RA subjects (73% female; mean age 58 years) were followed for a mean of 15 and 17 years (total: 8842 and 10,101 person-years), respectively. At baseline, RA subjects were significantly more likely to be former or current smokers when compared to non-RA subjects (p<0.001). Male gender, smoking, and personal cardiac history had weaker associations with CV events among RA subjects, compared to non-RA subjects. There was no significant difference between RA and non-RA subjects in the risk imparted with respect to the other CV risk factors (ie, family cardiac history, hypertension, dyslipidaemia, body mass index, or diabetes mellitus). CONCLUSION: While some traditional CV risk factors imparted similar risk among RA compared with non-RA subjects, others (ie, male gender, smoking and personal cardiac history) imparted significantly less risk for the development of CV disease. These differences in the overall impact of traditional CV risk factors suggest that strategies to prevent CV disease and mortality focused solely on controlling traditional CV risk factors may be relatively less beneficial in RA subjects than in the general population. Further research is needed to determine optimal approaches to reducing CV morbidity and mortality in persons with RA.

Management strategy for very mild aortic valve stenosis.

It is unclear how often patients with very mild aortic stenosis (gradients < 25 mmHg) need interval follow-up. The purpose of this study was to define the determinants of disease severity progression and to propose appropriate management strategies. It is known that congenital aortic stenosis is a progressive disease that requires long-term follow-up at consistent intervals. We studied 89 patients with very mild aortic stenosis. Cox proportional hazard modeling was performed to ascertain predictors of morbidity and mortality. Events were defined as valve surgery or death. Of the original 89 patients, 7 died (92% survival); one death was sudden and unexplained and six were noncardiac. Eighteen individuals were lost to follow-up (10 not located and 8 refused participation). Twelve (17%) had valve surgery. The minimum time interval between initial diagnosis of very mild aortic stenosis and surgery was 4.6 years (mean, 14.0). Age at diagnosis, gender, initial gradient, initial gradient/age, and aortic regurgitation were found not to be predictive of outcome. However, the slope of the transaortic gradient [change of gradient/time (years)] was predictive of outcome (hazard ratio of 1.69; confidence interval, 1.4-2.2). At least 17% of these patients progress to require operation. For patients with a gradient slope < 1.1, evaluation every 4 or 5 years is recommended. For patients with a gradient slope > 1.2, evaluation every 1 or 2 years seems prudent.

Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment.

BACKGROUND: The management of unruptured intracranial aneurysms is controversial. Investigators from the International Study of Unruptured Intracranial Aneurysms aimed to assess the natural history of unruptured intracranial aneurysms and to measure the risk associated with their repair. METHODS: Centres in the USA, Canada, and Europe enrolled patients for prospective assessment of unruptured aneurysms. Investigators recorded the natural history in patients who did not have surgery, and assessed morbidity and mortality associated with repair of unruptured aneurysms by either open surgery or endovascular procedures. FINDINGS: 4060 patients were assessed-1692 did not have aneurysmal repair, 1917 had open surgery, and 451 had endovascular procedures. 5-year cumulative rupture rates for patients who did not have a history of subarachnoid haemorrhage with aneurysms located in internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2. 6%, 14 5%, and 40% for aneurysms less than 7 mm, 7-12 mm, 13-24 mm, and 25 mm or greater, respectively, compared with rates of 2 5%, 14 5%, 18 4%, and 50%, respectively, for the same size categories involving posterior circulation and posterior communicating artery aneurysms. These rates were often equalled or exceeded by the risks associated with surgical or endovascular repair of comparable lesions. Patients' age was a strong predictor of surgical outcome, and the size and location of an aneurysm predict both surgical and endovascular outcomes. INTERPRETATION: Many factors are involved in management of patients with unruptured intracranial aneurysms. Site, size, and group specific risks of the natural history should be compared with site, size, and age-specific risks of repair for each patient.

Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years.

OBJECTIVE: To investigate the trends in incidence of extra-articular rheumatoid arthritis (ExRA) in a well defined community based cohort of patients with rheumatoid arthritis (RA), and to examine possible predictors of ExRA occurrence. METHODS: Using the resources of the Rochester Epidemiology Project, a retrospective medical record review was conducted of a cohort of 609 cases of RA in Olmsted County, MN, diagnosed during 1955-94. These cases had been previously classified using the ACR 1987 criteria for RA. Patients were followed up from 1955 to 2000 (median follow up 11.8 years; range 0.1-42.8), and incident ExRA manifestations were recorded according to predefined criteria. Time to first presentation of ExRA was compared in patients with RA by decade of diagnosis. Possible ExRA risk factors were identified in case record reviews. RESULTS: ExRA occurred in 247 patients (40.6%). A subgroup of 78 patients (12.8%) had ExRA manifestations considered to be severe in a previous study from Malmö, Sweden. The incidence of severe ExRA did not change significantly over the decades (p=0.165). In a multivariate analysis the main predictors of severe ExRA were smoking at RA diagnosis (risk ratio (RR)=2.94; 95% confidence interval (95% CI) 1.68 to 5.13) and early disability (Steinbrocker class III-IV at diagnosis) (RR=2.45; 95% CI 1.51 to 4.00). The effect of smoking overwhelmed the weaker effect of rheumatoid factor seropositivity. CONCLUSION: There was no decrease in the incidence of extra-articular manifestations in patients with RA diagnosed up to 1995. Smoking and early disability are independent risk factors for extra-articular RA.

Variations in bone density among persons of African heritage.

The epidemiology of bone loss in populations of African heritage is still poorly known. We compared a convenience sample of 47 African-American (AA) residents of Rochester, Minnesota (32 women, 15 men) and 66 recent immigrants from Somalia (all women) with 684 white subjects (349 women, 335 men) previously recruited from an age-stratified random sample of community residents. Areal bone mineral density (BMD, g/cm(2)) and volumetric bone mineral apparent density (BMAD, g/cm(3)) were determined for lumbar spine and proximal femur using the Hologic QDR 2000 for white subjects and the QDR 4500 for the others; the instruments were cross-calibrated from data on 20 volunteers. Lumbar spine BMD was 18% higher in AA ( p<0.001) and 4% lower in Somali ( p = 0.147) than white women. Femoral neck BMD was 27% higher in AA women but also 11% greater in Somali women (both p<0.001) compared with whites. Lumbar spine BMD was 6% higher ( p = 0.132) and femoral neck BMD 21% higher ( p<0.001) in AA than white men. No Somali men were studied. After correcting for bone size differences, both lumbar spine ( p<0.01) and femoral neck BMAD ( p<0.001) were greater for Somali than white women, but the difference between Somali and AA women persisted. Lumbar spine and femoral neck BMAD values also remained significantly greater for AA women (both p<0.001) and men ( p<0.05; p<0.001) compared with whites. Weight was associated with BMAD at both skeletal sites in all groups, but adjustment for differences in weight did not reduce the discrepancy in BMAD values between Somali and AA women or between the latter group and whites. This heterogeneity among different ethnic groups of African heritage may provide an opportunity for research to better explain race-specific differences in bone metabolism.

Secondary osteoporosis and the risk of distal forearm fractures in men and women.

Secondary osteoporosis plays an important role in the pathogenesis of hip and spine fractures, but relatively little is known about the potential impact of secondary osteoporosis and fall-related disorders on the risk of distal forearm fractures. To address this issue, we conducted a population-based, nested case-control study comparing 496 Rochester, Minnesota, residents with an initial distal forearm fracture to an equal number of age- and gender-matched controls. Potential risk factors were assessed by review of each subject's complete (inpatient and outpatient) medical records in the community (median duration >30 years) and analyzed using multiple logistic regression. Although history of diabetes mellitus in women (odds ratio [OR] 0.34, 95% confidence interval [CI] 0.15-0.75) and long-term anticonvulsant use in both genders (OR 3.58, 95% CI 1.26-10) were independently associated with fracture risk in a multivariate analysis, the conditions linked with secondary osteoporosis had, in aggregate, no statistically significant association with distal forearm fractures. Fall-related conditions altogether were associated with a borderline increase in risk (OR 1.36, 95% CI 0.98-1.91) and might have accounted for 19% of forearm fracture occurrence in the community. Among women (OR 2.72, 95% CI 1.20-6.19), but not men, a history of prior osteoporotic fracture was also associated with an increase in distal forearm fractures. These factors do not appear to account for the discrepancy in forearm fracture incidence in women when compared with men.

Correlates of osteoprotegerin levels in women and men.

Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds the final effector for osteoclastogenesis, receptor activator of NF-kappaB ligand (RANK-L). OPG production is regulated by a number of cytokines and hormones, including sex steroids, but there are few data on age and gender effects on circulating serum OPG levels, as well as possible relationships between OPG levels and bone turnover markers or bone mineral density (BMD). Thus, we measured serum OPG levels in an age-stratified, random sample of men (n = 346 age range, 23-90 years) and women (n = 304; age range 21-93 years) and related them to sex steroid levels, bone turnover markers and BMD. Serum OPG levels increased with age in both men (R = 0.39, p < 0.001) and women (R = 0.18, p < 0.01). Premenopausal women had higher OPG levels than men under age 50 years (171 +/- 6 pg/ml vs 134 +/- 6 pg/ml, respectively, p < 0.001), whereas serum OPG levels were no different in postmenopausal women compared with men = 50 years (195 +/- 7 pg/ml vs 188 +/- 7 pg/ml, respectively, p = 0.179). OPG levels correlated inversely with serum bioavailable testosterone levels in men = 50 years (R = -0.27, p < 0.001), but no associations were present with either estrogen or testosterone levels in the women. In the men, there was a trend for OPG levels to be associated positively with bone resorption markers and inversely with BMD. Collectively, the gender difference in OPG levels suggests that sex steroids may regulate OPG production in vivo, as has been found in vitro. Moreover, OPG production may also rise with increases in bone turnover, probably as a homeostatic mechanism to limit bone loss. Further studies directly testing these hypotheses should provide additional insights into the potential role of OPG in bone loss related to aging and sex steroid deficiency.

Effect of estrogen versus testosterone on circulating osteoprotegerin and other cytokine levels in normal elderly men.

Recent studies have shown that estrogen (E) likely plays a dominant role in inhibiting bone resorption in normal elderly men. Because both E and T inhibit osteoclast development and activity, stimulate osteoclast apoptosis, and inhibit osteoblast production of IL-6, it is unclear why T is less potent than E in inhibiting bone resorption in vivo. Osteoprotegerin (OPG) binds to and inactivates RANKL, the final mediator of osteoclastogenesis. In vitro, OPG production is stimulated by E, and preliminary data suggest that T has the opposite effect. Thus, we analyzed serum for OPG levels from a study in which 59 elderly men (mean age, 68 yr) were made acutely hypogonadal using a GnRH agonist and were also placed on an aromatase inhibitor to block conversion of androgens to estrogens. They were studied first under conditions of physiologic E and T replacement, and then randomized to no replacement, replacement with E alone, T alone, or both E and T. E alone resulted in an 18.6 +/- 7.9% (mean +/- SEM) increase in serum OPG levels (P < 0.05), whereas T alone tended to decrease OPG levels (by 10.0 +/- 8.5%; P < 0.05 compared with E alone). Using a two-factor ANOVA model, there was a highly significant T effect (P = 0.006) on decreasing serum OPG levels. Serum TNF-alpha, IL-6, and IL-6 soluble receptor levels increased significantly in the men who had both E and T withdrawn, and the increases in TNF-alpha and IL-6sR were absent in the men treated with either E or T. However, due to the variability in these cytokine measurements, the ANOVA models were not significant for E or T effects. Taken together, these data suggest that in vivo, T decreases OPG levels, whereas E tends to have the opposite effect. These differential effects of E vs. T on OPG production may explain, at least in part, why T has weaker effects than E on inhibiting bone resorption in vivo in humans.

Predictors of bone mineral density in aging healthy men varies by skeletal site.

Factors contributing to the pathogenesis of osteoporosis in women are well defined. However, changes in bone mineral metabolism in aging men and the role of various factors in the pathogenesis of age-related bone loss in men are less well understood. To further clarify these changes, serum and urine biochemical parameters, and lumbar spine, hip, and total body bone mineral density (BMD) were evaluated in a small sample of 45 healthy men aged 20-80 years, and multiple regression models were developed to predict age-related bone loss. Serum calcium, phosphate, albumin, creatinine clearance, osteocalcin, C-terminal propeptide of type I procollagen, log-free androgen index, dehydroepiandrosterone sulfate (DHEA-S), and androstenedione decreased with age, and serum sex hormone binding globulin and urine total and free pyridinoline increased with age. Femoral neck BMD decreased with age, but remained stable at the other sites measured. Multiple regression analysis indicated that serum phosphate, DHEA-S, and intact parathyroid hormone (PTH) predicted lumbar spine BMD. Age, serum phosphate, and PTH predicted femoral neck BMD. Urine-free deoxypyridinoline alone predicted femoral greater trochanter BMD. Weight, serum creatinine, and urine-free deoxypyridinoline predicted total body BMD. We conclude that predictor variables of bone density vary by skeletal site in healthy men. Alterations in adrenal androgens, phosphate, and PTH may be important in the pathogenesis of bone loss with aging in men.

Effect of time since onset of risk factors on the occurrence of ischemic stroke.

OBJECTIVE: To determine the effect of time since onset of risk factors on the modeling of risk factors for ischemic stroke. METHODS: The resources of the Rochester Epidemiology Project allowed identification of the 1,397 incident cases of ischemic stroke and age- and sex-matched control subjects from the population for 1970 through 1989. These cases and controls permitted the development of a multiple conditional logistic regression model to estimate the odds ratios of ischemic stroke for various risk factors. The time since onset variables for each risk factor were then added to the model to determine which were significant and to assess their impact on variables in the model. RESULTS: The time since onset variables for congestive heart failure and TIA were the only variables of this type included in the resultant model. Each showed the highest risk for stroke soon after the onset of the risk factor. In addition, the influence of congestive heart failure was higher at younger ages. Hypertension (with or without left ventricular hypertrophy) increases the risk for stroke but has a diminishing influence with increasing age. In addition, persons with left ventricular hypertrophy are at a higher risk than those with hypertension alone, although this difference also decreases with age. The time since onset variables pertaining to systolic hypertension at 140 to 159 mm Hg, 160 to 179 mm Hg, and > or =180 mm Hg were not significant in any analysis. CONCLUSIONS: TIA and congestive heart failure were the only risk factors for stroke for which time since onset was significant in the model for predicting ischemic stroke.

Incidence of venous thromboembolism in hospitalized patients vs community residents.

OBJECTIVE: To estimate the incidence rates of deep venous thrombosis (DVT) and pulmonary embolism (PE) in hospitalized patients and to compare these with incidence rates in community residents. PATIENTS AND METHODS: We performed a retrospective review of the complete medical records from a population-based inception cohort of patients who resided in Olmsted County, Minnesota, and had an incident DVT or PE from 1980 through 1990. RESULTS: From 1980 through 1990, 911 Olmsted County residents experienced their first lifetime event of definite, probable, or possible venous thromboembolism. Of these residents, 253 had been hospitalized for some reason other than a diagnosis of DVT or PE (in-hospital cases), and 658 were not hospitalized at onset of venous thromboembolism (community residents). The average annual age- and sex-adjusted incidence of in-hospital venous thromboembolism was 960.5 (95% confidence interval, 795.1-1125.9) per 10,000 person-years and was more than 100 times greater than the incidence among community residents at 7.1 (95% confidence interval, 6.5-7.6) per 10,000 person-years. The incidence of venous thromboembolism rose markedly with increasing age for both groups, with PE accounting for most of the age-related increase among in-hospital cases. Incidence rates in the 2 groups changed little over time despite a reduction in the average length of hospital stay between 1980 and 1990. CONCLUSIONS: Venous thromboembolism is a major national health problem, especially among elderly hospitalized patients. This finding emphasizes the need for accurate identification of hospitalized patients at risk for venous thromboembolism and a better understanding of the mechanisms involved so that safe and effective prophylaxis can be implemented.

Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals.

Elderly individuals are at high risk for morbidity and mortality when infected with influenza virus. Vaccinations with inactivated virus are less effective in the elderly due to the declining competency of the aging immune system. We have explored whether immunological parameters predict poor anti-influenza virus vaccine responses and can be used as biological markers of immunosenescence. One hundred fifty-three residents of community-based retirement facilities aged 65 to 98 years received a trivalent influenza vaccine. Vaccine-induced antibody responses were determined by comparing hemagglutination inhibition titers before and 28 days after immunization. The composition of the T-cell compartment was analyzed by flow cytometry and the sizes of three T-cell subsets, CD4(+) CD45RO(+) cells, CD4(+) CD28(null) cells, and CD8(+) CD28(null) cells, were determined. Only 17% of the vaccine recipients were able to generate an increase in titers of antibody to all three vaccine components, and 46% of the immunized individuals failed to respond to any of the three hemagglutinins. The likelihood of successful vaccination declined with age and was independently correlated with the expansion of a particular T-cell subset, CD8(+) CD28(null) T cells. The sizes of the CD4(+) CD45RO(+) memory T-cell and CD4(+) CD28(null) T-cell subsets had no effect on the ability to mount anti-influenza virus antibody responses. Frequencies of CD8(+) CD28(null) T cells are useful biological markers of compromised immunocompetence, identifying individuals at risk for insufficient antibody responses.

Clinical manifestations and survival rates among patients with saccular intracranial aneurysms: population-based study in Olmsted County, Minnesota, 1965 to 1995.

OBJECTIVE: To report presenting clinical symptoms, previous medical history, and survival rates for people with saccular intracranial aneurysms (IAs), in a defined population. METHODS: The medical records of all residents of Olmsted County, Minnesota, with possible IAs were reviewed. Clinical manifestations at the time of diagnosis, previous medical history, demographic factors, and survival rates after diagnosis were determined. RESULTS: Of 270 people with IAs detected between 1965 and 1995, 188 exhibited symptoms at the time of diagnosis, including 74% of women and 63% of men (P = 0.054). Intracranial hemorrhage (ICH) was the most common presenting symptom (60% of all patients and 86% of patients who exhibited symptoms), followed by cranial nerve palsy, transient ischemic attacks, and seizures. Survival rates after detection (with the exclusion of cases that were first detected during autopsies) were dependent on the occurrence of ICH; 23% of patients who presented with ICH died by 1 day after diagnosis, compared with 5% of those who did not exhibit symptoms or exhibited symptoms but without ICH at presentation. At 5 years, 44.7% of patients with hemorrhage had died, compared with 29.4% of patients with symptoms other than hemorrhage. After the first 24 hours after detection, survival rates did not differ significantly for those presenting with or without hemorrhage. Predictors of better survival rates also included lower age and later calendar year of presentation. CONCLUSION: This study provides the first data on aneurysm characteristics, clinical symptoms, and survival rates among people with IAs in a defined population. During the study period, most aneurysms were detected in the context of an aneurysm-related symptom (particularly among women), with a large proportion of patients presenting with ICH. After the acute phase of hemorrhage, long-term survival rates among people with IAs were similar for those presenting with or without ICH.

Role of serum leptin, insulin, and estrogen levels as potential mediators of the relationship between fat mass and bone mineral density in men versus women.

Although fat mass is related to bone mineral density (BMD), the potential mechanism(s) of this effect remain to be defined. Thus, we assessed the role of the candidate hormones, leptin, insulin, and estrogen in mediating fat mass effects on the skeleton. Specifically, we related these hormones and fat mass to BMD at the total hip, mid-lateral spine, and mid-distal radius in a sample of 137 premenopausal women (age range 21-54 years), 165 postmenopausal women (34-93 years), and 343 men (23-90 years) recruited from the general population. Fat mass and BMD were significantly related in pre- and postmenopausal women at multiple sites, whereas this relationship was only weakly present in men at the total hip. Serum leptin levels were also significantly related to BMD in the women, but not in the men. Insulin was associated with hip BMD in the women, and bioavailable estradiol (E2) was correlated with BMD at all sites in men and in postmenopausal women. In the women, adjusting for leptin reduced the strength of the association between fat mass and BMD, with further adjustments for insulin or bioavailable E2 having no additional effects. Adjusting for leptin in the men had no consistent effect on the relationship between fat mass and BMD. Collectively, these data suggest that there is a sexual dimorphism in the relationship of fat mass and leptin to BMD, with both being positively associated with BMD in women but not in men. In women, leptin may also mediate at least part of the protective effect of fat mass on the skeleton.

Relationship of serum sex steroid levels to longitudinal changes in bone density in young versus elderly men.

Estrogen appears to play an important role in determining bone mineral density in men, but it remains unclear whether estrogen primarily determines peak bone mass or also affects bone loss in elderly men. Thus, we assessed longitudinal rates of change in bone mineral density in young (22-39 yr; n = 88) vs. elderly (60-90 yr; n = 130) men and related these to circulating total and bioavailable estrogen and testosterone levels. In young men bone mineral density increased significantly over 4 yr at the mid-radius and ulna and at the total hip (by 0.32-0.43%/yr), whereas it decreased in the elderly men at the forearm sites (by 0.49-0.66%/yr), but did not change at the total hip. The rate of increase in bone mineral density at the forearm sites in the young men was significantly correlated to serum total and bioavailable estradiol and estrone levels (r = 0.22-0.35), but not with total or bioavailable testosterone levels. In the elderly men the rates of bone loss at the forearm sites were most closely associated with serum bioavailable estradiol levels (r = 0.29-0.33) rather than bioavailable testosterone levels. Moreover, elderly men with bioavailable estradiol levels below the median [40 pmol/liter (11 pg/ml)] had significantly higher rates of bone loss and levels of bone resorption markers than men with bioavailable estradiol levels above 40 pmol/liter. These data thus indicate that estrogen plays a key role both in the acquisition of peak bone mass in young men and in bone loss in elderly men. Moreover, our findings suggest that age-related decreases in bioavailable estradiol levels to below 40 pmol/liter may well be the major cause of bone loss in elderly men. This subset of men is perhaps most likely to benefit from preventive therapy.

Aortic valve sclerosis and aortic atherosclerosis: different manifestations of the same disease? Insights from a population-based study.

OBJECTIVES: The aim of this study was to examine the association between atherosclerosis risk factors, aortic atherosclerosis and aortic valve abnormalities in the general population. BACKGROUND: Clinical and experimental studies suggest that aortic valve sclerosis (AVS) is a manifestation of the atherosclerotic process. METHODS: Three hundred eighty-one subjects, a sample of the Olmsted County (Minnesota) population, were examined by transthoracic and transesophageal echocardiography. The presence of AVS (thickened valve leaflets), elevated transaortic flow velocities and aortic regurgitation (AR) was determined. The associations between atherosclerosis risk factors, aortic atherosclerosis (imaged by transesophageal echocardiography) and aortic valve abnormalities were examined. RESULTS: Age, male gender, body mass index (odds ratio [OR]: 1.07 per kg/m(2); 95% confidence interval [CI]: 1.02 to 1.12), antihypertensive treatment (OR: 1.93; CI: 1.12 to 3.32) and plasma homocysteine levels (OR: 1.89 per twofold increase; CI: 0.99 to 3.61) were independently associated with an increased risk of AVS. Age, body mass index and pulse pressure (OR: 1.21 per 10 mm Hg; CI: 1.00 to 1.46) were associated with elevated (upper quintile) transaortic velocities, whereas only age was independently associated with AR. Sinotubular junction sclerosis (p = 0.001) and atherosclerosis of the ascending aorta (p = 0.03) were independently associated with AVS and elevated transaortic velocities, respectively. CONCLUSIONS: Atherosclerosis risk factors and proximal aortic atherosclerosis are independently associated with aortic valve abnormalities in the general population. These observations suggest that AVS is an atherosclerosis-like process involving the aortic valve.

The epidemiology of venous thromboembolism in the community.

The incidence of venous thromboembolism exceeds 1 per 1000; over 200,000 new cases occur in the United States annually. Of these, 30% die within 30 days; one-fifth suffer sudden death due to pulmonary embolism. Despite improved prophylaxis, the incidence of venous thromboembolism has been constant since 1980. Independent risk factors for venous thromboembolism include increasing age, male gender, surgery, trauma, hospital or nursing home confinement, malignancy, neurologic disease with extremity paresis, central venous catheter/transvenous pacemaker, prior superficial vein thrombosis, and varicose veins; among women, risk factors include pregnancy, oral contraceptives, and hormone replacement therapy. About 30% of surviving cases develop recurrent venous thromboembolism within ten years. Independent predictors for recurrence include increasing age, obesity, malignant neoplasm, and extremity paresis. About 28% of cases develop venous stasis syndrome within 20 years. To reduce venous thromboembolism incidence, improve survival, and prevent recurrence and complications, patients with these characteristics should receive appropriate prophylaxis.

Bone density in an immigrant population from Southeast Asia.

The epidemiology of bone loss in populations of Asian heritage is still poorly known. This study compared the skeletal status of a convenience sample of 396 Southeast Asian immigrants (172 Vietnamese, 171 Cambodians and 53 Laotians) residing in Rochester, Minnesota in 1997 with 684 white subjects previously recruited from an age-stratified random sample of community residents. Areal bone mineral density (BMD, g/cm2) and volumetric bone mineral apparent density (BMAD, g/cm3) were determined for lumbar spine and proximal femur using the Hologic QDR 2000 instrument for the white population and the QDR 4500 for Southeast Asian subjects; the machines were cross-calibrated from data on 20 volunteers. Lumbar spine BMD was 7% higher in white than Southeast Asian women (p < 0.001), and similar results were observed for the femoral neck; lumbar spine BMD was 12% higher in white than nonwhite men (p < 0.001). Race-specific discrepancies were reduced by calculating BMAD: for premenopausal women, lumbar spine and femoral neck differences between whites and Southeast Asians were eliminated; for postmenopausal women the lumbar spine differences persisted (p < 0.0001), while femoral neck BMAD was actually higher for Southeast Asians. There were no race-specific differences in femoral neck BMAD among men of any age (p = 0.312), but lumbar spine BMAD was less for younger (p = 0.042) but not older (p = 0.693) Southeast Asian men. There were differences among the Southeast Asian subgroups, but no clear pattern emerged. Predictors of lumbar spine BMAD in Southeast Asian women were age (p < 0.001), weight (p = 0.015) and gravidity (p = 0.037). Even after adjusting for bone size using BMAD, 32% and 9% of Southeast Asian women and men, respectively, would be considered to have osteoporosis at the femoral neck and 25% and 4%, respectively, at the lumbar spine. These findings indicate a need for culturally sensitive educational interventions for Southeast Asians and for physicians to pursue diagnosis and treatment to prevent osteoporosis-related disabilities in this population.

Genetic similarity in inflammatory and degenerative abdominal aortic aneurysms: a study of human leukocyte antigen class II disease risk genes.

PURPOSE: Clinically, abdominal aortic aneurysms (AAAs) display a spectrum of inflammation that extends from apparently noninflamed (degenerative) AAAs to the classic inflammatory variant. Genes encoded in the human leukocyte antigen (HLA) region are important in the development of both variants of AAA; however, their role in progression to the inflammatory variant is unknown. The purpose of this study was to compare HLA class II genes in patients with degenerative versus classic inflammatory AAAs and to quantify their impact as disease risk factors. METHODS: Genotypes of the 12 major alleles of the HLA-DR B1 locus were determined in patients with degenerative (102) and inflammatory (40) AAAs who were compared with controls (118). Univariate and multivariate logistic regression analyses were used to determine allele distributions and to quantify disease risk. RESULTS: Distribution of the HLA-DR B1 alleles was nonrandom and similar in both degenerative and inflammatory AAA groups compared with controls. The B1*02 and B1*04 alleles were enhanced in both degenerative (39.2% vs. 25.4%, P =.03; and 35.3% vs. 24.6%, P =.08 respectively) and inflammatory (47.5% vs. 25.4%, P =.01; and 32.5% vs. 24.6%, P =.09, respectively) AAAs compared with controls. The B1*02 and B1*04 alleles were associated with risk for both degenerative (odds ratio [OR] 2.2; 95% CI, 1.2-4.0; and OR 2.0; 95% CI, 1.1-3.7, respectively) and inflammatory AAAs (OR 3.7; 95% CI, 1.8-8.6; and OR 2.5; 95% CI, 1.1-6.1). CONCLUSION: This study demonstrates that identical HLA alleles function as genetic risk factors for both inflammatory and degenerative AAAs. These results support the concept of a common, immune-mediated pathogenesis for AAAs that may be modulated by HLA-independent factors.

Lymphoid neogenesis in rheumatoid synovitis.

In rheumatoid arthritis (RA), tissue-infiltrating lymphocytes can be arranged in sophisticated organizations that resemble microstructures usually formed in secondary lymphoid organs. Molecular pathways and host risk factors involved in this process of lymphoid neogenesis remain to be defined. In a series of 64 synovial tissue biopsies, lymphoid follicles with germinal centers (GCs) were found in 23.4% of the patients. Follicular dendritic cells (FDCs) were exclusively present in tissues with GCs, suggesting that the recruitment or in situ maturation of FDCs is a critical factor for GC formation in the synovial membrane. Primary follicles were absent, emphasizing the role of Ag recognition in the generation of inflammation-associated lymphoid organogenesis. Multivariate logistic regression analysis of tissue cytokines and chemokines identified two parameters, in situ transcription of lymphotoxin (LT)-beta and of B lymphocyte chemoattractant (BLC; BLC/CXCL13), that were predictors for FDC recruitment and synovial GC formation. LT-beta and BLC/CXCL13 were found to be independent variables that could, in part, compensate for each other to facilitate GC formation. Prediction models incorporating in situ transcription of LT-beta and BLC/CXCL13 had high negative yet moderate positive predictive values, suggesting that LT-beta and BLC/CXCL13 are necessary but not sufficient. LT-beta protein was detected on a subset of mantle zone and GC B cells, but also on T cells in follicular structures. BLC/CXCL13 was produced by FDCs in follicular centers, but was predominantly found in endothelial cells and synovial fibroblasts, suggesting heterotypic signaling between cells of the synovial membrane and infiltrating lymphocytes in regulating extranodal lymphoid neogenesis.