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Nader Rifai

Publications and source records attributed to Nader Rifai.

At least 19 recordsLinked to original sources
PubMed2006

Multiple biomarkers for the prediction of first major cardiovascular events and death.

BACKGROUND: Few investigations have evaluated the incremental usefulness of multiple biomarkers from distinct biologic pathways for predicting the risk of cardiovascular events. METHODS: We measured 10 biomarkers in 3209 participants attending a routine examination cycle of the Framingham Heart Study: the levels of C-reactive protein, B-type natriuretic peptide, N-terminal pro-atrial natriuretic peptide, aldosterone, renin, fibrinogen, D-dimer, plasminogen-activator inhibitor type 1, and homocysteine; and the urinary albumin-to-creatinine ratio. RESULTS: During follow-up (median, 7.4 years), 207 participants died and 169 had a first major cardiovascular event. In Cox proportional-hazards models adjusting for conventional risk factors, the following biomarkers most strongly predicted the risk of death (each biomarker is followed by the adjusted hazard ratio per 1 SD increment in the log values): B-type natriuretic peptide level (1.40), C-reactive protein level (1.39), the urinary albumin-to-creatinine ratio (1.22), homocysteine level (1.20), and renin level (1.17). The biomarkers that most strongly predicted major cardiovascular events were B-type natriuretic peptide level (adjusted hazard ratio, 1.25 per 1 SD increment in the log values) and the urinary albumin-to-creatinine ratio (1.20). Persons with "multimarker" scores (based on regression coefficients of significant biomarkers) in the highest quintile as compared with those with scores in the lowest two quintiles had elevated risks of death (adjusted hazard ratio, 4.08; P<0.001) and major cardiovascular events (adjusted hazard ratio, 1.84; P=0.02). However, the addition of multimarker scores to conventional risk factors resulted in only small increases in the ability to classify risk, as measured by the C statistic. CONCLUSIONS: For assessing risk in individual persons, the use of the 10 contemporary biomarkers that we studied adds only moderately to standard risk factors.

Biomarkers↗
PubMed2006

Cardiac troponin increases among runners in the Boston Marathon.

STUDY OBJECTIVE: Studies indicate that running a marathon can be associated with increases in serum cardiac troponin levels. The clinical significance of such increases remains unclear. We seek to determine the prevalence of troponin increases and epidemiologic factors associated with these increases in a large and heterogeneous cohort of marathon finishers. METHODS: Entrants in the 2002 Boston Marathon were recruited 1 to 2 days before the race. Data collected included demographic and training history, symptoms experienced during the run, and postrace troponin T and I levels. Simple descriptive statistics were performed to describe the prevalence of troponin increases and runner characteristics. RESULTS: Of 766 runners enrolled, 482 had blood analyzed at the finish line. In all, 34% were women, 20% were younger than 30 years, and 92% had run at least 1 previous marathon. Most runners (68%) had some degree of postrace troponin increase (troponin T > or = 0.01 ng/mL or troponin I > or = 0.1 ng/mL), and 55 (11%) had significant increases (troponin T > or = 0.075 ng/mL or troponin I > or = 0.5 ng/mL). Running inexperience (< 5 previous marathons) and young age (< 30 years) were associated with elevated troponins. These correlates were robust throughout a wide range of troponin thresholds considered. Health factors, family history, training, race performance, and symptoms were not associated with increases. CONCLUSION: Troponin increases were relatively common among marathon finishers and can reach levels typically diagnostic for acute myocardial infarction. Less marathon experience and younger age appeared to be associated with troponin increases, whereas race duration and the presence of traditional cardiovascular risk factors were not. Further work is needed to determine the clinical significance of these findings.

Adult↗
PubMed2006

Lipoprotein(a), measured with an assay independent of apolipoprotein(a) isoform size, and risk of future cardiovascular events among initially healthy women.

CONTEXT: Controversy exists as to whether lipoprotein(a), a lipoprotein with homology to plasminogen, is a clinically meaningful cardiovascular risk marker in women. There is also poor agreement among lipoprotein(a) levels obtained by different assays. OBJECTIVE: To determine the association of lipoprotein(a) levels, measured with an assay independent of apolipoprotein(a) isoform size, with the incidence of future cardiovascular events. DESIGN, SETTING, AND PARTICIPANTS: Prospective study of 27,791 initially healthy women in the Women's Health Study, enrolled between November 1992 and July 1995 and followed up for 10 years. Lipoprotein(a) level was measured in blood samples obtained at baseline with an assay independent of apolipoprotein(a) isoform size. MAIN OUTCOME MEASURE: Hazard ratios (HRs) for first-ever major cardiovascular events (nonfatal myocardial infarction, nonfatal cerebrovascular event, coronary revascularization, or cardiovascular deaths). RESULTS: During follow-up, there were 899 incident cardiovascular events. After adjusting for age, smoking, blood pressure, body mass index, total cholesterol, high-density lipoprotein cholesterol, diabetes, hormone use, C-reactive protein, and randomization treatment groups, women in the highest quintile of lipoprotein(a) (> or =44.0 mg/dL) were 1.47 times more likely (95% CI, 1.21-1.79; P for trend <.001) to develop cardiovascular events than women in the lowest quintile (< or =3.4 mg/dL). This association, however, was due almost entirely to a threshold effect among those with the highest lipoprotein(a) levels. After adjusting for all of the variables listed above, the HR associated with lipoprotein(a) levels exceeding the 90th percentile (> or =65.5 mg/dL) was 1.66 (95% CI, 1.38-1.99); 95th percentile (> or =83 mg/dL), 1.87 (95% CI, 1.50-2.34); and 99th percentile (> or =130.7 mg/dL), 1.99 (95% CI, 1.32-3.00), with almost no risk gradient at lower levels. Associations were strongest among women with low-density lipoprotein cholesterol (LDL-C) above the median level. In this subgroup, the adjusted HR associated with lipoprotein(a) levels exceeding the 90th percentile was 1.81 (95% CI, 1.48-2.23); 95th percentile, 1.93 (95% CI, 1.51-2.48); and 99th percentile, 1.93 (95% CI, 1.21-3.05) (P value for interaction with LDL-C = .001). CONCLUSIONS: In this cohort of initially healthy women, extremely high levels of lipoprotein(a) (> or =90th percentile), measured with an assay independent of apolipoprotein(a) isoform size, were associated with increased cardiovascular risk, particularly in women with high levels of LDL-C. However, the threshold and interaction effects observed do not support routine measurement of lipoprotein(a) for cardiovascular stratification in women.

Apolipoproteins↗
PubMed2006

Is plasma oxidized low-density lipoprotein, measured with the widely used antibody 4E6, an independent predictor of coronary heart disease among U.S. men and women?

OBJECTIVES: Our aim was to examine whether circulating oxidized low-density lipoprotein (oxLDL) is a predictor of coronary heart disease (CHD) independent of lipid markers and to compare oxLDL, apolipoprotein B100 (apoB), and total cholesterol (TC)/high-density lipoprotein-cholesterol (HDL-C) ratio as predictors of CHD. BACKGROUND: Measurement of circulating oxLDL with antibody 4E6, has been widely used in many studies; however, few large prospective studies have examined whether this marker is a predictor of CHD independent of lipids and compared oxLDL with other important lipid predictors. METHODS: After 6 years of follow-up among 18,140 men from the HPFS (Health Professionals Follow-up Study) and 8 years among 32,826 women from the Nurses' Health Study who provided blood samples at baseline, we identified incident nonfatal myocardial infarction or fatal CHD in 266 men and 235 women. Each case was matched with two control subjects by age, smoking, and time of blood draw. The oxLDL was measured via enzyme-linked immunosorbent assay with antibody 4E6 against oxidized apoB. RESULTS: Among both men and women, oxLDL was significantly related to risk of CHD in multivariate analysis before adjustment for any lipid markers. However, when oxLDL, LDL cholesterol, HDL-C, and triglycerides were mutually adjusted, oxLDL was no longer predictive. When oxLDL and apoB were mutually adjusted, only apoB was predictive of CHD. Similar results were found when oxLDL and TC/HDL-C ratio were mutually adjusted. CONCLUSIONS: Our results suggest that circulating oxLDL, measured with antibody 4E6, is not an independent overall predictor of CHD after adjustment of lipid markers and is less predictive in development of CHD than apoB and TC/HDL-C ratio.

Aged↗
PubMed2006

Relation between soluble intercellular adhesion molecule-1, statin therapy, and long-term risk of clinical cardiovascular events in patients with previous acute coronary syndrome (from PROVE IT-TIMI 22).

High levels of adhesion molecules, such as soluble intercellular adhesion molecule-1 (sICAM-1), are associated with long-term risk of cardiac events in patients with and without stable coronary artery disease. The relation between sICAM-1 and long-term risk after acute coronary syndromes (ACSs) and the influence of statin treatment has not been explored. Using a nested case-control design, patients with ACS who were enrolled in the PROVE IT-TIMI 22 trial were matched for age, gender, smoking, diabetes, type of ACS presentation, and revascularization for index event (583 patients with recurrent events vs 581 controls). Patients with recurrent events were identified as such by death, myocardial infarction, or hospitalization for recurrent ACS. Soluble ICAM-1 was measured at study entry (approximately 7 days after ACS). After adjusting for statin regimen and other risk factors, patients in quartiles 2 to 4 were at a higher risk of clinical events compared with those in quartile 1 (odds ratio 1.6 for quartile 4 vs 1, 95% confidence interval 1.1 to 2.3, p = 0.02). The risk of adverse events in patients with sICAM-1 levels in quartiles 2 to 4 was most marked in subjects who were allocated to standard dose statin therapy, even after adjusting for low-density lipoprotein cholesterol and C-reactive protein at day 30. The risk in quartiles 2 to 4 was somewhat attenuated in the intensive therapy group. In conclusion, in this large study of patients with ACS, we provide evidence that increased endothelial activation after ACS is independently associated with increased long-term risk of death, myocardial infarction, or recurrent ACS.

Angina, Unstable↗
PubMed2006

Additive value of immunoassay-measured fibrinogen and high-sensitivity C-reactive protein levels for predicting incident cardiovascular events.

BACKGROUND: Current guidelines suggest measuring high-sensitivity C-reactive protein (hs-CRP) as an aid to coronary risk assessment in adults without cardiovascular disease (CVD). Whether other inflammatory biomarkers, such as fibrinogen, add further prognostic information is uncertain. METHODS AND RESULTS: In a prospective study of 27,742 initially healthy middle-aged women, the associations of baseline immunoassay fibrinogen and hs-CRP measurements with incident CVD were examined over a 10-year follow-up period. Compared with women in the bottom biomarker quintile, age-adjusted hazard ratios (95% confidence intervals [CIs]) for incident CVD for quintiles 2 to 5 of fibrinogen were 1.10 (0.86 to 1.41), 1.30 (1.03 to 1.65), 1.46 (1.16 to 1.85), and 2.43 (1.95 to 3.02); for hs-CRP they were 1.48 (1.06 to 2.05), 1.70 (1.24 to 2.33), 2.20 (1.63 to 2.96), and 3.24 (2.43 to 4.31). After further adjustment for established risk factors, both biomarkers remained associated (P for trend < or = 0.001) with incident CVD (hazard ratio, 1.35; 95% CI, 1.07 to 1.71 for top fibrinogen quintile; and hazard ratio, 1.68; 95% CI, 1.22 to 2.29 for top hs-CRP quintile compared with the bottom quintiles). Further adjustment for the other biomarker resulted in hazard ratios of 1.23 and 1.56 (P for trend = 0.02 and 0.002), respectively. Although fibrinogen correlated positively with hs-CRP (rs = 0.41, P < 0.001), the highest CVD risk was associated with elevated levels of both fibrinogen and hs-CRP: age-adjusted hazard ratio of 3.45 (95% CI, 2.60 to 4.57) for women with fibrinogen > 393 mg/dL and hs-CRP > 3 mg/L compared with < 329 mg/dL and < 1 mg/L, respectively. CONCLUSIONS: In this cohort of initially healthy women, baseline levels of fibrinogen measured with a high-quality immunoassay provided additive value to hs-CRP and traditional risk factors in predicting incident CVD.

Biomarkers↗
PubMed2006

Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial.

BACKGROUND: Elevated levels of high-sensitivity C-reactive protein (hsCRP) are associated with higher risk of adverse outcomes in patients at risk for or with established coronary artery disease. Retrospective analyses suggest that this risk may be modified with statin therapy. However, a role for hsCRP in monitoring the success of therapy remains uncertain. METHODS AND RESULTS: We measured the serum concentration of hsCRP at 30 days (n=3813) and 4 months in patients with non-ST-elevation or ST-elevation acute coronary syndrome randomly assigned to an early intensive versus delayed conservative simvastatin strategy in the Aggrastat-to-Zocor Trial. Patients with hsCRP >3 mg/L at 30 days had significantly higher 2-year mortality rates than those with hsCRP 1 to 3 mg/L or hsCRP <1 mg/L (6.1% versus 3.7% versus 1.6%, P<0.0001). Results were similar with hsCRP measured at 4 months. After adjusting for age, gender, diabetes, smoking, cardiovascular history, index event, lipid levels, and randomly assigned treatment, patients with hsCRP >3 mg/L were at more than 3-fold higher risk of death (HR, 3.7; 95% CI, 1.9 to 7.2) compared with those with hsCRP <1 mg/L. "Average" levels of hsCRP (1 to 3 mg/L) were also associated with increased risk compared with those with hsCRP <1 mg/L (HR, 2.3; 95% CI, 1.2 to 4.6). Patients allocated to early intensive statin therapy were more likely to achieve hsCRP levels <1 mg/L at 30 days (P=0.028) and 4 months (P<0.0001). CONCLUSIONS: Achieved levels of hsCRP at 30 days and 4 months after acute coronary syndrome are independently associated with long-term survival. Patients treated with more aggressive statin therapy are more likely to achieve lower levels of hsCRP.

Acute Disease↗
PubMed2006

Associations of the apolipoprotein A1/C3/A4/A5 gene cluster with triglyceride and HDL cholesterol levels in women with type 2 diabetes.

The apolipoprotein gene cluster (APOA1/C3/A4/A5) was recently associated with triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) in non-diabetic population. Little is known whether the variations in these genes affect lipid homeostasis in patients with type 2 diabetes. We examined the associations of 10 polymorphisms at APOA1/C3/A4/A5 gene cluster with blood lipids among 902 diabetic women. A linkage disequilibrium (LD) breakdown was observed between APOA5 and other genes. APOA5 S19W was associated with significantly higher fasting TG levels (P=0.001). Two common haplotypes encompassing four APOA5 polymorphisms (SNP1, SNP2, S19W, and SNP3) were associated with 35.6 mg/dL (haplotype 2212, APOA5*2, P=0.016) and 57.8 mg/dL (haplotype 1121, APOA5*3, P=0.0002) higher fasting TG levels compared with the most common (haplotype 1111, APOA5*1), respectively. Adjustment for age, BMI, and other covariates did not appreciably change such associations. In addition, APOC3 promoter polymorphism -455T/C showed significant associations with fasting TG levels (P=0.006), whereas APOA4 +347T/A showed significant associations with lower levels of HDL-C (P=0.017). Our results indicate that the variability in APOA1/C3/A4/A5 gene cluster may affect TG and HDL levels in women with type 2 diabetes.

Adult↗
PubMed2006

Valsartan, blood pressure reduction, and C-reactive protein: primary report of the Val-MARC trial.

Increased levels of high-sensitivity C-reactive protein (hsCRP) are associated with incident hypertension as well as cardiovascular events, and angiotensin II is a potent proinflammatory mediator. However, whether angiotensin receptor blockade lowers hsCRP is uncertain. We performed a randomized trial in which 1668 patients with stage 2 hypertension were treated with 160 mg valsartan or 160/12.5 mg valsartan/hydrochlorothiazide (HCTZ) once daily for 2 weeks with forced titration to 320 mg valsartan or 320/12.5 mg valsartan/HCTZ for an additional 4 weeks. After 6 weeks, systolic blood pressure (-25 versus -18 mm Hg; P<0.001) and diastolic blood pressure (-14 versus -9 mm Hg; P<0.001) were reduced to a greater degree among those allocated to valsartan/HCTZ than to valsartan monotherapy. The median change in hsCRP was -0.12 mg/L among those allocated to valsartan compared with +0.05 mg/L among those allocated to valsartan/HCTZ, a 13.3% difference (P<0.001); this difference between valsartan and valsartan/HCTZ was present in all subgroups evaluated despite the fact that blood pressure reduction was greater in the combined therapy group. No relationship was observed between hsCRP reduction and blood pressure; in all analyses, the proportion of variation in change in hsCRP with valsartan monotherapy explained by change in blood pressure was <2%. Thus, in this prospective trial, valsartan reduced hsCRP levels in a manner independent of degree of blood pressure reduction. These data raise the hypothesis that angiotensin receptor blockade may have anti-inflammatory effects in addition to blood pressure-lowering effects.

Adult↗
PubMed2006

Inflammation and changes in metabolic syndrome abnormalities in US adolescents: findings from the 1988-1994 and 1999-2000 National Health and Nutrition Examination Surveys.

BACKGROUND: Understanding of C-reactive protein (CRP) in adult metabolic syndrome is increasing; however, this relationship in children is less clear. METHODS: We compared the prevalence of metabolic abnormalities and metabolic syndrome in fasting 12- to 19-year-olds from the 1999-2000 and 1988-1994 National Health and Nutrition Examination Survey (NHANES). In the more recent dataset we explored the relationship between metabolic abnormalities and CRP as measured by a high-sensitivity assay. RESULTS: The prevalence of central obesity, low HDL-cholesterol, and hypertension increased between the 2 surveys. Three or more abnormalities (metabolic syndrome) were found in 12.7% [95% confidence interval (CI), 10.0%-15.4%] of fasting adolescents from the 1999-2000 survey, compared with 9.2% (95% CI, 7.8%-10.6%; P < 0.001) in the 1988-1994 dataset, with increases also seen in sex and ethnic/racial subgroups. Increases in metabolic syndrome were primarily attributable to increasing body mass index (BMI); prevalence of BMI at or above the 85th percentile increased from 25.9% to 30.5%. Metabolic syndrome was much more prevalent in overweight compared with normal-weight adolescents (38.6% vs 1.4%; P < 0.001). Median CRP increased with increasing numbers of metabolic abnormalities and was higher in adolescents with metabolic syndrome than in those without. CRP was higher in adolescents with BMI at or above the 85th percentile than those with normal BMI. CONCLUSIONS: Metabolic abnormalities and the metabolic syndrome phenotype are increasingly prevalent in US adolescents, attributable in part to the increasing incidence of overweight. Adolescents with more metabolic abnormalities have higher CRP, which may be an indicator of greater metabolic derangement and future cardiovascular risk.

Adolescent↗
PubMed2006

A prospective study of hemoglobin A1c concentrations and risk of breast cancer in women.

Impaired glucose metabolism and hyperinsulinemia have been hypothesized to increase breast cancer risk. However, findings from observational studies relating blood concentrations of hyperinsulinemia markers to breast cancer risk have been inconsistent. We prospectively evaluated whether hemoglobin A1c (HbA1c) concentrations predict breast cancer risk in a large female cohort. We included 27,110 female participants of the Women's Health Study who were, at baseline, free of cancer and had usable blood specimens as well as sufficient information on potential risk factors for breast cancer. Relative risks (RR) and 95% confidence intervals (95% CI) were estimated from Cox proportional hazards regression models. All Ps were two sided. During an average of 10 years of follow-up, 790 incident cases of invasive breast cancer were confirmed. Higher baseline HbA1c levels were not associated with an increased risk of breast cancer. The multivariate RR for the highest relative to the lowest quintile of HbA1c levels was 0.87 (95% CI, 0.69-1.10; P(trend) = 0.22). Higher HbA1c levels were also not associated with an increased risk of breast cancer according to alternative clinical cutoff points for HbA1c or in the analyses stratified by body mass index or according to certain tumor characteristics. However, a weakly inverse association was noted among postmenopausal women, especially among those who had never used hormone therapy. There was also a weakly inverse association between HbA1c levels and estrogen receptor-negative breast tumors. These data suggest that higher HbA1c concentrations do not seem to increase risk of breast cancer among apparently healthy women.

Adult↗
PubMed2006

Frequency of clinically unsuspected myocardial injury at a children's hospital.

BACKGROUND: Ill children are at risk but rarely screened for myocardial injury. The frequency of such injury in ill children is unknown. Elevated levels of plasma cardiac troponin I (cTnI) can detect subclinical myocardial injury. METHODS: We measured cTnI levels from 283 Children's Hospital, Boston patients (median age 2.10 years, range 0.13-22.4 years) seen in an outpatient or emergency clinic without clinically apparent cardiac disease. We took > or = 0.5 ng/mL as an indication of myocardial injury. We also measured plasma creatine kinase-MB, total creatine kinase, and myoglobin, and performed a chart review. RESULTS: Fifteen (7.8%) of the 193 acutely ill children and 4 (4.4%) of the 90 well children had an elevated cTnI level (P = .44). Within the acutely ill group, the children with elevated cTnI were younger and had lower mean hemoglobin and hematocrit levels. Cardiac troponin I levels correlated with creatine kinase-MB (r = 0.22; P < .001) but not with creatine kinase or myoglobin. The 4 children with cTnI > 0.89 ng/mL, who also had plasma cardiac troponin T measured, showed cardiac troponin T elevations that were consistent with unstable angina levels in adults. Four children had high-level cTnI elevations (> 2 ng/mL) consistent with acute myocardial infarction levels in adults. CONCLUSIONS: Elevated cTnI levels occur in children without clinically apparent cardiac disease and can be at adult unstable angina or acute myocardial infarction levels. Prospective studies to determine the clinical significance of these findings and their relationship to the development of cardiomyopathy are warranted.

Adolescent↗
PubMed2006

Protein biomarker discovery and validation: the long and uncertain path to clinical utility.

Better biomarkers are urgently needed to improve diagnosis, guide molecularly targeted therapy and monitor activity and therapeutic response across a wide spectrum of disease. Proteomics methods based on mass spectrometry hold special promise for the discovery of novel biomarkers that might form the foundation for new clinical blood tests, but to date their contribution to the diagnostic armamentarium has been disappointing. This is due in part to the lack of a coherent pipeline connecting marker discovery with well-established methods for validation. Advances in methods and technology now enable construction of a comprehensive biomarker pipeline from six essential process components: candidate discovery, qualification, verification, research assay optimization, biomarker validation and commercialization. Better understanding of the overall process of biomarker discovery and validation and of the challenges and strategies inherent in each phase should improve experimental study design, in turn increasing the efficiency of biomarker development and facilitating the delivery and deployment of novel clinical tests.

Animals↗
PubMed2006

Soluble intercellular adhesion molecules, soluble vascular cell adhesion molecules, and risk of coronary heart disease.

OBJECTIVE: We examined the association of circulating levels of soluble intercellular adhesion molecules (sICAM-1) and soluble vascular cell adhesion molecules (sVCAM-1) with coronary heart disease (CHD) risk factors and whether the adhesion molecules alone, and in combination, can serve as predictors of coronary CHD. RESEARCH METHODS AND PROCEDURES: Among 18,225 men from the Health Professional Follow-up Study who provided blood in 1994, we documented 266 incidents of non-fatal myocardial infarction or fatal CHD during 6 years of follow-up. The cases were matched 1:2 with non-cases on age, smoking, and month of blood draw. We found both adhesion molecules directly associated with BMI, inflammatory biomarkers, and triglycerides and inversely associated with high-density lipoprotein and alcohol intake (p < 0.05). After adjustment for C-reactive protein, cholesterol-to-high-density lipoprotein ratio, age, smoking, BMI, physical activity, alcohol intake, history of diabetes, parental history of CHD, aspirin use, antihypertensive drug use, and fasting status, the relative risk of CHD was 1.69 [95% confidence interval (CI), 1.14 to 2.51] for sICAM-1 and 1.34 (95% CI, 0.91 to 1.96) for sVCAM-1, when comparing the top quintile with the lower four quintiles. Control for other inflammatory or lipid biomarkers did not appreciably attenuate the associations. When we cross-classified participants based on their sICAM-1 and sVCAM-1 levels, only the men in the top quintile of both biomarkers [relative risk = 2.39 (95% CI, 1.45 to 3.91)] had a significantly elevated risk of CHD (P interaction = 0.01, multivariate model). DISCUSSION: sICAM-1 and sVCAM-1 are directly associated with obesity and other CHD risk factors. The combination of high levels of both adhesion molecules might be associated with the development of CHD, independent of other CHD risk factors.

Aged↗
PubMed2006

Mechanisms and biomarkers of cardiovascular injury induced by phosphodiesterase inhibitor III SK&F 95654 in the spontaneously hypertensive rat.

The cardiovascular injury of the type III selective PDE inhibitor SK&F 95654 was investigated in SHR. Twenty-four hours after a single sc injection of 100 or 200 mg/kg of the drug, rats exhibited cardiomyocyte necrosis and apoptosis, interstitial inflammation, hemorrhage and edema, as well as mesenteric arterial hemorrhage and necrosis, periarteritis, EC and VSMC apoptosis, EC activation, and MC activation and degranulation. Elevated serum levels of cTnT and decreased cTnT immunoperoxidase staining on cardiomyocytes were detected in the drug-treated rats. Serum levels of alpha2-macroglobulin and IL-6 were significantly elevated following drug treatment. NMR spectral patterns of urine samples are significantly different between the drug-treated and control rats. These results indicate that measurement of serum cTnT, acute phase proteins, and cytokines as well as metabonomic urine profiles may serve as potential biomarkers for drug-induced cardiovascular injury in rats. Increased expression of CD63 on MC (tissue biomarker of MC), of nitrotyrosine on MC and EC (an indirect indicator of NO in vivo), and of iNOS on MC and EC (source of NO) suggest that NO produced by activated and degranulated MC as well as activated EC play an important role in SK&F 95654-induced mesenteric vascular injury.

Alanine Transaminase↗
PubMed2006

Functional decline in patients with and without peripheral arterial disease: predictive value of annual changes in levels of C-reactive protein and D-dimer.

BACKGROUND: Inflammation may be a potential mechanism of aging-related functional decline. We determined whether greater annual increases in levels of high sensitivity C-reactive protein (hsCRP) and D-dimer predicted greater decline in functioning among persons with and without lower extremity peripheral arterial disease (PAD). METHODS: We prospectively studied 296 men and women with PAD and 191 without PAD. Objective measures of functioning, hsCRP, and D-dimer were obtained at baseline and annually for 3 years (mean follow-up = 36.3 +/- 6.4 months). RESULTS: Among PAD participants, greater annual increases in hsCRP were associated with greater annual declines in 6-minute walk performance (-2.63 ft/mg/L, p =.039) but not in other functional outcomes. Higher prior year absolute hsCRP levels were associated with greater declines in 6-minute walk (-2.93 ft/mg/L, p =.022), summary performance score (-0.038/mg/L, p =.017), and rapid paced 4-meter walk (-0.29 cm/s/mg/L, p =.026) during the subsequent year. Among participants without PAD, greater annual increases in hsCRP were associated with greater annual declines in 6-minute walk (-7.47 ft/mg/L, p =.002), usual-pace 4-meter walk (-0.33 cm/s/mg/L, p <.001), fast paced 4-meter walk (-0.56 cm/s/mg/L, p =.003), and the summary performance score (-0.029 mg/L, p <.001). There were no consistent associations between D-dimer levels and functional decline. CONCLUSION: These findings suggest that inflammation may play a role in functional decline in persons with and without PAD.

Aged↗
PubMed2006

C-peptide, insulin-like growth factor binding protein-1, glycosylated hemoglobin, and the risk of distal colorectal adenoma in women.

BACKGROUND: Determinants of insulin secretion and insulin-like growth factors (IGF) have been directly associated with risk for colorectal cancer. However, few studies have evaluated whether these factors are also associated with risk of colorectal adenoma, the main precursor lesion to colorectal cancer. METHODS: We identified 380 distal colorectal adenoma cases diagnosed between 1989 and 1998 and 380 controls among nondiabetic women from the cohort of 32,826 women, nested in the Nurses' Health Study, who provided blood samples in 1989 to 1990. Cases and controls were individually matched on year of birth, time period of and indication(s) for endoscopy, and date of blood draw. RESULTS: High concentrations of C-peptide, an indicator of insulin secretion, were statistically significantly associated with risk of distal colorectal adenoma [multivariable relative risk (MVRR) top versus bottom quartile, 1.63; 95% confidence interval (95% CI), 1.01-2.66; P = 0.01], even after including body mass index and physical activity in the statistical model. Fasting IGF binding protein-1 (IGFBP-1) concentrations did not show any clear association with risk for adenoma (MVRR top versus bottom quartile, 1.08; 95% CI, 0.56-2.07). These associations did not differ significantly by size/stage of adenoma. Glycosylated hemoglobin (HbA1c) was associated with a nonstatistically significant increased risk of colorectal adenoma (MVRR top versus bottom quartile, 1.47; 95% CI, 0.89-2.44). CONCLUSIONS: High HbA1c and low IGFBP-1 were not clearly associated with increased risk of distal colorectal adenoma. However, our current results and previous associations between C-peptide and colorectal cancer suggest that hyperinsulinemia may play a role throughout the development of colorectal neoplasia.

Adenoma↗