Does late gadolinium enhancement predict cardiac events in patients with ischemic cardiomyopathy?
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Adult↗
Biomedical subjects
Ralph D'Agostino
Publications and source records attributed to Ralph D'Agostino.
Stent revascularization for the prevention of cardiovascular and renal events among patients with renal artery stenosis and systolic hypertension: rationale and design of the CORAL trial.
BACKGROUND: Atherosclerotic renal artery stenosis is a problem with no consensus on diagnosis or therapy. The consequences of renal ischemia are neuroendocrine activation, hypertension, and renal insufficiency that can potentially result in acceleration of atherosclerosis, further renal dysfunction, myocardial infarction, heart failure, stroke, and death. Whether revascularization improves clinical outcomes when compared with optimum medical therapy is unknown. METHODS: CORAL is a randomized clinical trial contrasting optimum medical therapy alone to stenting with optimum medical therapy on a composite cardiovascular and renal end point: cardiovascular or renal death, myocardial infarction, hospitalization for congestive heart failure, stroke, doubling of serum creatinine, and need for renal replacement therapy. The secondary end points evaluate the effectiveness of revascularization in important subgroups of patients and with respect to all-cause mortality, kidney function, renal artery patency, microvascular renal function, and blood pressure control. We will also correlate stenosis severity with longitudinal renal function and determine the value of stenting from the perspectives of quality of life and cost-effectiveness. The primary entry criteria are (1) an atherosclerotic renal stenosis of > or = 60% with a 20 mm Hg systolic pressure gradient or > or = 80% with no gradient necessary and (2) systolic hypertension of > or = 155 mm Hg on > or = 2 antihypertensive medications. Randomization will occur in 1080 subjects. The study has 90% power to detect a 28% reduction in primary end point hazard rate. CONCLUSIONS: CORAL represents a unique opportunity to determine the incremental value of stent revascularization, in addition to optimal medical therapy, for the treatment of atherosclerotic renal artery stenosis.
Angioplasty, Balloon↗
Phase I-II prospective dose-escalating trial of lycopene in patients with biochemical relapse of prostate cancer after definitive local therapy.
OBJECTIVES: To report a prospective trial of lycopene supplementation in biochemically relapsed prostate cancer. METHODS: A total of 36 men with biochemically relapsed prostate cancer were enrolled in a dose-escalating, Phase I-II trial of lycopene supplementation. Six consecutive cohorts of 6 patients each received daily supplementation with 15, 30, 45, 60, 90, and 120 mg/day for 1 year. The serum levels of prostate-specific antigen (PSA) and plasma levels of lycopene were measured at baseline and every 3 months. The primary endpoints were PSA response (defined as a 50% decrease in serum PSA from baseline), pharmacokinetics, and the toxicity/tolerability of this regimen. RESULTS: A total of 36 patients were enrolled. The median age was 74 years (range 56 to 83), with a median serum PSA at entry of 4.4 ng/mL (range 0.8 to 24.9). No serum PSA responses were observed, and 37% of patients had PSA progression. The median time to progression was not reached. Toxicity was mild, with 1 patient discontinuing therapy because of diarrhea. Significant elevations of plasma lycopene were noted at 3 months and then appeared to plateau for all six dose levels. The plasma levels for doses between 15 and 90 mg/day were similar, with additional elevation only at 120 mg/day. CONCLUSIONS: Lycopene supplementation in men with biochemically relapsed prostate cancer is safe and well tolerated. The plasma levels of lycopene were similar for a wide dose range (15 to 90 mg/day) and plateaued by 3 months. Lycopene supplementation at the doses used in this study did not result in any discernible response in serum PSA.
Adenocarcinoma↗
Surfactant trials.
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Biological Products↗
Spatial learning and memory deficits after whole-brain irradiation are associated with changes in NMDA receptor subunits in the hippocampus.
Whole-brain irradiation is used for the treatment of brain tumors, but can it also induce neural changes, with progressive dementia occurring in 20-50% of long-term survivors. The present study investigated whether 45 Gy of whole-brain irradiation delivered to 12-month-old Fischer 344 x Brown Norway rats as nine fractions over 4.5 weeks leads to impaired Morris water maze (MWM) performance 12 months later. Compared to sham-irradiated rats, the irradiated rats demonstrated impaired MWM performance. The relative levels of the NR1 and NR2A but not the NR2B subunits of the NMDA receptor were significantly higher in hippocampal CA1 of irradiated rats compared to control rats. No significant differences were detected for these NMDA subunits in CA3 or dentate gyrus. Further analysis of CA1 revealed that the relative levels of the GluR1 and GluR2 subunits of the AMPA receptor and synaptophysin were not altered by whole-brain irradiation. In summary, a clinically relevant regimen of fractionated whole-brain irradiation led to significant impairments in spatial learning and reference memory and alterations in the relative levels of subunits of the NMDA, but not the AMPA, receptors in hippocampal CA1. These findings suggest for the first time that radiation-induced cognitive impairments may be associated with alterations in glutamate receptor composition.
Animals↗
The natural course of beta-cell function in nondiabetic and diabetic individuals: the Insulin Resistance Atherosclerosis Study.
Data from the UKPDS (U.K. Prospective Diabetes Study) indicate a continuous decline in beta-cell function in patients with type 2 diabetes. We studied longitudinal changes in beta-cell function (follow-up of 5.2 years) in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes, using acute insulin response (AIR) and insulin sensitivity index (S(i)) from a frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40-69 years. At baseline, decreasing levels of both S(i) and AIR (either unadjusted or adjusted for S(i)) mirrored deteriorating glucose tolerance status at baseline and at follow-up. A different pattern was found with respect to longitudinal changes; S(i) declined in each glucose tolerance category, ranging from -0.81 x10(-4) min(-1) x muU(-1) x ml(-1) in NGT at baseline and NGT at follow-up (NGT/NGT) to -1.06 x10(-4) in NGT/diabetes, whereas the directional change in AIR principally determined the glucose tolerance status at follow-up. In NGT/NGT S(i) decreased by 35% and AIR increased by 34%. Results were similar in each of the three ethnic groups. These data shed light on the natural course of beta-cell function; over 5.2 years, mean insulin sensitivity declined in each glucose tolerance category. The change in AIR, however, principally determined glucose tolerance status at follow-up; NGT was maintained by a compensatory increase in insulin secretion. Failure to increase insulin secretion led to IGT, and a decrease in insulin secretion led to overt diabetes. This data may have important implications for the prevention and treatment of type 2 diabetes.
Atherosclerosis↗
Weight loss in overweight adults and the long-term risk of hypertension: the Framingham study.
BACKGROUND: Few studies address long-term effects of weight loss on risk of incident hypertension among overweight adults. METHODS: We evaluated weight loss among 623 overweight (body mass index [calculated as weight in kilograms divided by the square of height in meters] >/=25) middle-aged (aged 30-49 years) and 605 overweight older (aged 50-65 years) adults in Framingham, Mass. Subjects were classified first according to amount of weight lost over 4 years: (1) weight changed by less than 1.8 kg (stable weight), (2) lost 1.8 to less than 3.6 kg, (3) lost 3.6 to less than 6.8 kg, and (4) lost 6.8 kg or more. We also classified weight loss according to whether it was sustained during the next 4 years. RESULTS: After adjusting for age, sex, education, baseline body mass index, height, activity, smoking, and alcohol intake, weight loss of 6.8 kg or more led to a 21% to 29% reduction in long-term hypertension risk. After adjusting for cancer or cardiovascular disease occurring during follow-up, weight loss of 6.8 kg or more led to a 28% reduction in risk (relative risk [95% confidence interval], 0.72 [0.49-1.05]) for middle-aged adults and a 37% reduction (0.63 [0.42-0.95]) for older adults. Sustained weight loss led to a 22% reduction in hypertension risk (0.78 [0.60-1.03]) among middle-aged and a 26% reduction (0.74 [0.56-0.97]) in older adults. This risk reduction was strengthened by adjustment for prevalent cancer or cardiovascular disease during follow-up. CONCLUSION: A modest weight loss, particularly when sustained, substantially lowers the long-term risk of hypertension in overweight adults.
Adult↗
Measures of brain morphology and infarction in the framingham heart study: establishing what is normal.
Numerous anatomical and brain imaging studies find substantial differences in brain structure between men and women across the span of human aging. The ability to extend the results of many of these studies to the general population is limited, however, due to the generally small sample size and restrictive health criteria of these studies. Moreover, little attention has been paid to the possible impact of brain infarction on age-related differences in regional brain volumes. Given the current lack of normative data on gender and aging related differences in regional brain morphology, particularly with regard to the impact of brain infarctions, we chose to quantify brain MRIs from more than 2200 male and female participants of the Framingham Heart Study who ranged in age from 34 to 97 years. We believe that MRI analysis of the Framingham Heart Study more closely represents the general population enabling more accurate estimates of regional brain changes that occur as the consequence of normal aging. As predicted, men had significantly larger brain volumes than women, but these differences were generally not significant after correcting for gender related differences in head size. Age explained approximately 50% of total cerebral brain volume differences, but age-related differences were generally small prior to age 50, declining substantially thereafter. Frontal lobe volumes showed the greatest decline with age (approximately 12%), whereas smaller differences were found for the temporal lobes (approximately 9%). Age-related differences in occipital and parietal lobe were modest. Age-related gender differences were generally small, except for the frontal lobe where men had significantly smaller lobar brain volumes throughout the age range studied. The prevalence of MRI infarction was common after age 50, increased linearly with age and was associated with significantly larger white matter hyperintensity (WMH) volumes beyond that associated with age-related differences in these measures. Amongst men, the presence of MRI infarction was associated with significant age-related reductions in total brain volume. Finally, statistically significant associations were found between the volume of MRI infarcts in cubic centimeters and all brain measures with the exception of parietal lobe volume for individuals where the volume of MRI infarctions was measured. These data serve to define age and gender differences in brain morphology for the Framingham Heart Study. To the degree participants of the Framingham Heart Study are representative the general population, these data can serve as norms for comparison with morphological brain changes associated with aging and disease. In this regard, these cross-sectional quantitative estimates suggest that age-related tissue loss differs quantitatively and qualitatively across brain regions with only minor differences between men and women. In addition, MRI evidence of cerebrovascular disease is common to the aging process and associated with smaller regional brain volumes for a given age, particularly for men. We believe quantitative MRI studies of the Framingham community enables exploration of numerous issues ranging from understanding normal neurobiology of brain aging to assessing the impact of various health factors, particularly those related to cerebrovascular disease, that appear important to maintaining brain health for the general population.
Adult↗
Dietary patterns and the metabolic syndrome in obese and non-obese Framingham women.
OBJECTIVES: To examine the relationship between habitual dietary patterns and the metabolic syndrome (MetS) in women and to identify foci for preventive nutrition interventions. RESEARCH METHODS AND PROCEDURES: Dietary patterns, nutrient intake, cardiovascular disease (CVD), and MetS risk factors were characterized in 1615 Framingham Offspring-Spouse Study (FOS) women. Dietary pattern subgroups were compared for MetS prevalence and CVD risk factor status using logistic regression and analysis of covariance. Analyses were performed overall in women and stratified on obesity status; multivariate models controlled for age, apolipoprotein E (APOE) genotypes, and CVD risk factors. RESULTS: Food and nutrient profiles and overall nutritional risk of five non-overlapping habitual dietary patterns of women were identified including Heart Healthier, Lighter Eating, Wine and Moderate Eating, Higher Fat, and Empty Calories. Rates of hypertension and low high-density lipoprotein levels were high in non-obese women, but individual MetS risk factor levels were substantially increased in obese women. Overall MetS risk varied by dietary pattern and obesity status, independently of APOE and CVD risk factors. Compared with obese or non-obese women and women overall with other dietary patterns, MetS was highest in those with the Empty Calorie pattern (contrast p value: p<0.05). DISCUSSION: This research shows the independent relationship between habitual dietary patterns and MetS risk in FOS women and the influence of obesity status. High overall MetS risk and the varying prevalence of individual MetS risk factors in female subgroups emphasize the importance of preventive nutrition interventions and suggest potential benefits of targeted behavior change in both obese and non-obese women by dietary pattern.
Abdomen↗
Combination of isosorbide dinitrate and hydralazine in blacks with heart failure.
BACKGROUND: We examined whether a fixed dose of both isosorbide dinitrate and hydralazine provides additional benefit in blacks with advanced heart failure, a subgroup previously noted to have a favorable response to this therapy. METHODS: A total of 1050 black patients who had New York Heart Association class III or IV heart failure with dilated ventricles were randomly assigned to receive a fixed dose of isosorbide dinitrate plus hydralazine or placebo in addition to standard therapy for heart failure. The primary end point was a composite score made up of weighted values for death from any cause, a first hospitalization for heart failure, and change in the quality of life. RESULTS: The study was terminated early owing to a significantly higher mortality rate in the placebo group than in the group given isosorbide dinitrate plus hydralazine (10.2 percent vs. 6.2 percent, P=0.02). The mean primary composite score was significantly better in the group given isosorbide dinitrate plus hydralazine than in the placebo group (-0.1+/-1.9 vs. -0.5+/-2.0, P=0.01; range of possible values, -6 to +2), as were its individual components (43 percent reduction in the rate of death from any cause [hazard ratio, 0.57; P=0.01] 33 percent relative reduction in the rate of first hospitalization for heart failure [16.4 percent vs. 22.4 percent, P=0.001], and an improvement in the quality of life [change in score, -5.6+/-20.6 vs. -2.7+/-21.2, with lower scores indicating better quality of life; P=0.02; range of possible values, 0 to 105]). CONCLUSIONS: The addition of a fixed dose of isosorbide dinitrate plus hydralazine to standard therapy for heart failure including neurohormonal blockers is efficacious and increases survival among black patients with advanced heart failure.
Adult↗
Comparison of the associations of apolipoprotein B and non-high-density lipoprotein cholesterol with other cardiovascular risk factors in patients with the metabolic syndrome in the Insulin Resistance Atherosclerosis Study.
BACKGROUND: The metabolic syndrome (MetS) as defined by the National Cholesterol Education Panel definition has been proposed as an indicator of cardiovascular disease risk. Both apolipoprotein (apo)B and non-HDL cholesterol (NHDLC) have been proposed as an additional indicator to identify patients at higher risk in MetS patients. METHODS AND RESULTS: We studied 1522 individuals in the Insulin Resistance Atherosclerosis Study (IRAS) who were 40 to 69 years of age and from 3 ethnic groups. Their anthropometric measures, lipids, apoB, C-reactive protein, fibrinogen, plasminogen activator inhibitor-1, fasting and post-glucose load glucose, and insulin concentrations were measured, and insulin sensitivity was determined by intravenous glucose tolerance test. Differences in risk parameters in individuals with hyper-apoB/normo-NHDLC, and normo-apoB/hyper-NHDLC were compared in all IRAS subjects and again in those with MetS. In both cases, despite anticipated lower LDL cholesterol, the hyper-apoB/normo-NHDLC group had elevated risk indicated by greater waist circumference (both P<0.05) and fasting insulin (P<0.01) and lower insulin sensitivity (P<0.001). They also had higher C-reactive protein (P<0.05). Moreover, the Spearman correlation of apoB was significantly stronger (P<0.05) in the direction of greater associated risk than that of NHDLC with body mass index, waist circumference, systolic blood pressure, 2-hour glucose, fasting glucose, fasting insulin, 2-hour insulin, insulin sensitivity, C-reactive protein, fibrinogen, and plasminogen activator inhibitor-1. CONCLUSIONS: In conclusion, apoB is more closely associated with central adiposity, insulin resistance, thrombosis, and inflammation than NHDLC. Our data suggest that apoB is a better candidate risk parameter than NHDLC for identifying a subgroup of individuals with or without MetS with elevated cardiovascular risk.
Adult↗
Prevalence and relevance of contact dermatitis allergens: a meta-analysis of 15 years of published T.R.U.E. test data.
BACKGROUND: The patch test procedure is frequently employed to help determine or confirm the cause of allergic contact dermatitis (ACD). The T.R.U.E. Test has become a global standard and is the commercially available patch test system currently used within the United States. Although many studies report T.R.U.E. Test data, none has measured the overall prevalence and relevance of reactions to the allergens tested by the T.R.U.E. Test. Our objective is to describe the prevalence and relevance of contact dermatitis allergens as tested by the T.R.U.E. Test. METHODS: We conducted a search of the MEDLINE database from 1966 to June 2000 for all publications on the use of the T.R.U.E. Test in the clinical evaluation of ACD in human subjects. Inclusion and exclusion criteria were applied. For each study, we identified and recorded the number of subjects tested, the number of patients with positive reactions, and the number with relevant reactions. Data were analyzed using the SAS system (Cary, NC). RESULTS: Ours is the first study to compile the entire corpus of published T.R.U.E. Test data and to examine these data using meta-analytic techniques. The meta-analysis shows that nickel (14.7% of tested patients), thimerosal (5.0%), cobalt (4.8%), fragrance mix (3.4%), and balsam of Peru (3.0%) are the most prevalent allergens. The 5 least prevalent allergens are paraben mix (0.5%), black rubber mix (0.6%), quaternium-15 (0.6%), quinoline mix (0.7%), and caine mix (0.7%). By contrast, North American Contact Dermatitis Data Group (NACDG) data show that the 5 most prevalent allergens are nickel (14.3%), fragrance mix (14%), neomycin (11.6%), balsam of Peru (10.4%), and thimerosal (10.4%). NACDG data indicate that the prevalence of allergy to cobalt is 9.2%. In order to assess the clinical importance of T.R.U.E. Test allergens, we employ the Significance-Prevalence Index Number (SPIN). Based on SPIN, the most clinically important allergens tested by the T.R.U.E. Test are nickel (SPIN=894), cobalt (266), fragrance mix (158), colophony (141), and thiuram mix (138). CONCLUSIONS: Our results identify the prevalence of common contact dermatitis allergens as tested by the T.R.U.E. Test and are in general agreement with previously published reports using other patch test methods. Over 3700 allergens have been identified as causing ACD, of which the T.R.U.E. Test tests only 23. Thus, the T.R.U.E. Test is a screening test at best. Comparison with NACDG data suggests that clinically important allergens may be missed by the T.R.U.E. Test.
Allergens↗
Monocyte cytokine production, systemic inflammation and cardiovascular disease in very elderly men and women: the Framingham Heart Study.
In very elderly participants of the Framingham Heart Study (mean age 79 years, 276 men and 462 women), interleukin-6 correlated with C-reactive protein (CRP) levels. Interleukin-6, tumour necrosis factor alpha and interleukin-1 production, and CRP were not associated with prevalent cardiovascular disease, and nonsteroidal anti-inflammatory drug use did not influence cytokine or CRP levels. Further studies are warranted to examine the prognostic implications of CRP and related cytokines for CVD in the elderly.
Aged↗
Differences in insulin resistance in nondiabetic subjects with isolated impaired glucose tolerance or isolated impaired fasting glucose.
Both impaired glucose tolerance (IGT) (as defined by the 1985 World Health Organization criteria) and impaired fasting glucose (IFG) (as defined by the 1997 American Diabetes Association criteria) represent intermediate metabolic states between normal and diabetic glucose homeostasis. Cardiovascular disease may be related to postglucose load rather than fasting glycemia, i.e., IGT rather than IFG. We hypothesized that subjects with IGT may be more insulin resistant and have higher levels of common cardiovascular risk factors than those with isolated IFG. In the Insulin Resistance Atherosclerosis Study (IRAS), we studied S(i) and first-phase insulin secretion (acute insulin response [AIR]), as derived from a frequently sampled intravenous glucose tolerance test, as well as common cardiovascular risk factors in four different glucose tolerance categories (NFG/NGT [n = 654], NFG/IGT [n = 255], IFG/NGT [n = 59], and IFG/IGT [n = 102]) among nondiabetic subjects. Subjects with isolated postchallenge hyperglycemia (NFG/IGT) had lower S(i) (means +/- SE: 2.10 +/- 0.04 vs. 2.59 +/- 0.13 x 10(-4) min(-1). microU(-1). ml(-1); P = 0.005), lower proinsulin levels (34.4 +/- 1.8 vs. 42.0 +/- 4.5 pmol/l; P = 0.03), higher AIR (273.1 +/- 18.1 vs. 215.9 +/- 30.0 pmol/l; P = 0.04), higher C-reactive protein (2.49 +/- 0.3 vs. 1.49 +/- 0.5 mg/l; P = 0.0015), and higher triglyceride levels (137.7 +/- 5.5 vs. 108.4 +/- 8.9 mg/dl; P = 0.0025) than subjects with isolated fasting hyperglycemia (IFG/NGT). The relation of insulin resistance to glucose tolerance category was consistently seen in women and men and across the three ethnic groups of the IRAS (non-Hispanic whites, African Americans, and Hispanics). Nondiabetic individuals with isolated postchallenge hyperglycemia (IGT) are more insulin resistant than individuals with isolated fasting hyperglycemia (IFG). The risk factor pattern (including increased insulin resistance) seen in isolated IGT identifies a subgroup of nondiabetic individuals who are likely to benefit from early intervention.
Adult↗
Insulin sensitivity, insulinemia, and coronary artery disease: the Insulin Resistance Atherosclerosis Study.
OBJECTIVE: The aim of this study was to evaluate whether low insulin sensitivity (Si) measured using a modified frequently sampled intravenous glucose tolerance test with minimal model analysis is associated with coronary artery disease (CAD) independent of other cardiovascular risk factors. RESEARCH DESIGN AND METHODS: We studied 1,482 women and men, age 40-69 years old, African American (28%), Hispanic (34%), or non-Hispanic white (38%), with normal (45%), impaired (23%), or diabetic (32%) glucose tolerance. CAD defined as confirmed past myocardial infarction, coronary artery bypass graft, coronary angioplasty, or presence of a major Q-wave was found in 91 participants. RESULTS: The odds ratio (OR) for CAD was greatest among individuals in the two lowest quintiles of Si (2.4, 95% CI 1.0-5.6 and 4.7, 2.1-10.7) compared with the highest Si quintile. After adjusting for demographic and cardiovascular risk factors, a decrement from the 75th to 25th percentile in Si was associated with a 56% increase in CAD (P=0.028). Similar increments in fasting or 2-h insulin levels were associated with, respectively, only 15 (NS) and 3% (NS) increases in CAD. The association between Si and CAD was partially mediated by insulin, HDL cholesterol and triglyceride levels, hypertension, diabetes, and obesity, but not LDL cholesterol or cigarette smoking. CONCLUSIONS: Low Si is associated with CAD independently of and stronger than plasma insulin levels. Part of the association is accounted for by dyslipidemia, hypertension, diabetes, and obesity.
Adult↗
Comparison of the associations of apolipoprotein B and low-density lipoprotein cholesterol with other cardiovascular risk factors in the Insulin Resistance Atherosclerosis Study (IRAS).
BACKGROUND: Risk factors for vascular disease include obesity, dyslipidemia, hypertension, dysglycemia, insulin resistance, inflammation, thrombosis, and subclinical atherosclerosis. This study compares the associations of apolipoprotein B (apoB) and LDL cholesterol (LDLC) with a wide array of measures of these risk factors. METHODS AND RESULTS: In 1522 individuals in the Insulin Resistance Atherosclerosis Study, anthropometric measures and measures of lipids, apoB, C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), fasting and postglucose load glucose and insulin concentrations, and carotid artery intima-media thickness (IMT) were taken and insulin sensitivity was determined by frequently sampled intravenous glucose tolerance test. There were significant differences in measures of abdominal obesity, dyslipidemia, hyperinsulinemia, and thrombosis between subjects with elevated apoB but normal LDLC versus those with elevated LDLC but normal apoB. In each statistically significant comparison, the elevated-apoB group had higher associated risk than the elevated-LDLC group. Moreover, apoB is highly significantly (P<0.0001) correlated with each measure in the direction of higher risk, whereas LDLC was significantly correlated (P<0.05) only with blood pressure, triglyceride, fibrinogen, and C-reactive protein. After further adjustment for LDLC, apoB correlations remained significant, whereas several LDLC correlations adjusted for apoB became significant in the direction of lower risk. CONCLUSIONS: Elevated apoB is more strongly associated than LDLC with other risk factors, including measures in the National Cholesterol Education Program guidelines for lipid treatment and other more recently established risk factors. This may provide new insight into why apoB is a better predictor of vascular risk than LDLC.
Adult↗
Cytokines, insulin-like growth factor 1, sarcopenia, and mortality in very old community-dwelling men and women: the Framingham Heart Study.
BACKGROUND: Aging is associated with increased production of catabolic cytokines, reduced circulating levels of insulin-like growth factor 1 (IGF-1), and acceleration of sarcopenia (loss of muscle with age). We hypothesized that these factors are independently linked to mortality in community-dwelling older persons. METHODS: We examined the relation of all-cause mortality to peripheral blood mononuclear cell production of inflammatory cytokines (tumor necrosis factor alpha [TNF-alpha], interleukin 1 beta, interleukin 6), serum interleukin 6 and IGF-1, and fat-free mass and clinical status in 525 ambulatory, free-living participants in the Framingham Heart Study. RESULTS: Of the 525 subjects (aged 72 to 92 years at baseline), 122 (23%) died during 4 years of follow-up. After adjusting for age, sex, comorbid conditions, smoking, and body mass index, mortality was associated with greater cellular production of TNF-alpha (hazard ratio [HR] = 1.27 per log(10) difference in ng/mL; 95% confidence interval [CI]: 1.00 to 1.61; P = 0.05) and higher serum interleukin 6 levels (HR = 1.30 per log(10) difference in pg/mL; 95% CI: 1.04 to 1.63]; P = 0.02), but not with higher serum IGF-1 levels (HR = 0.70 per log(10) difference in pg/mL; 95% CI: 0.49 to 0.99; P = 0.04). In a subset of 398 subjects (55 deaths) in whom change in fat-free mass index during the first 2 years was measured, less loss of fat-free mass and greater IGF-1 levels were associated with reduced mortality during the next 2 years. CONCLUSION: Greater levels or production of the catabolic cytokines TNF-alpha and interleukin 6 are associated with increased mortality in community-dwelling elderly adults, whereas IGF-1 levels had the opposite effect.
Aged↗
Inflammation in the prediabetic state is related to increased insulin resistance rather than decreased insulin secretion.
BACKGROUND: Elevated levels of proinflammatory proteins are predictive of both cardiovascular (CV) disease and type 2 diabetes. Previously, atherogenic changes in traditional CV risk factors in the prediabetic state were mainly seen in insulin-resistant subjects rather than in those with a predominant defect in insulin secretion. METHODS AND RESULTS: We studied in prediabetic individuals from the Insulin Resistance Atherosclerosis Study (IRAS) the relation of C-reactive protein (CRP), plasminogen activator inhibitor (PAI)-1, and fibrinogen to defects in insulin sensitivity (SI) and first-phase insulin secretion, respectively, as assessed using a frequently sampled intravenous glucose tolerance test. One hundred forty-eight of 906 (16.3%) nondiabetic individuals developed diabetes after a mean follow-up of 5.2 years. Prediabetic individuals who were insulin resistant had higher levels of PAI-1 (mean [95% CI], 25.83 ng/mL [22.42 to 29.77] versus 16.31 ng/mL [12.56 to 21.18]; P=0.003) and CRP (mean [95% CI], 2.88 mg/L [2.33 to 3.56] versus 1.68 mg/L [1.13 to 2.49]; P=0.018) than insulin-sensitive individuals, but individuals with decreased acute insulin response tended to have lower rather than higher levels of inflammatory proteins compared with those with high insulin secretion. Prediabetic subjects who were predominantly insulin resistant had higher levels of inflammatory proteins compared with both prediabetic subjects with decreased insulin secretion as well as nonconverters. By contrast, prediabetic subjects with a predominant defect in first-phase insulin secretion had levels of inflammatory proteins indistinguishable from those in nonconverters. CONCLUSIONS: We have shown an increased proinflammatory state in prediabetic individuals who are predominantly insulin resistant but not in those with a primary defect in beta-cell function. These results provide additional evidence that prediabetic subjects may be at an increased risk of heart disease, and this risk seems to be restricted to subjects with high insulin resistance.
Adipose Tissue↗