Showing papers by "Philimon Gona published in 2006"
TL;DR: The use of the 10 contemporary biomarkers that were studied adds only moderately to standard risk factors and only small increases in the ability to classify risk, as measured by the C statistic.
Abstract: 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.
1,286 citations
TL;DR: In this community-based sample, clinical variables explained 26% of the interindividual variation in CRP, whereas a common triallelic CRP SNP contributed modestly.
Abstract: Background— Serum C-reactive protein (CRP) level is a heritable complex trait that predicts incident cardiovascular disease. We investigated the clinical and genetic sources of interindividual variability in serum CRP. Methods and Results— We studied serum CRP in 3301 Framingham Heart Study (FHS) participants (mean age 61 years, 53% women). Twelve clinical covariates explained 26% of the variability in CRP level, with body mass index alone explaining 15% (P<0.0001) of the variance. To investigate the influence of genetic variation at the CRP gene on CRP levels, we first constructed a dense linkage disequilibrium map for common single-nucleotide polymorphisms (SNPs) spanning the CRP locus (1 SNP every 850 bases, 26 kilobase [kb] genomic region). Thirteen CRP SNPs were genotyped in 1640 unrelated FHS participants with measured CRP levels. After adjustment for clinical covariates, 9 of 13 SNPs were associated with CRP level (P<0.05). To account for correlation among SNPs, we conducted forward stepwise select...
223 citations
TL;DR: In a large community-based sample, a conservative strategy relating several biomarkers to vascular endothelial function identified plasma N-ANP as a key correlate of mean flow under basal conditions and of FMD in response to forearm cuff occlusion.
Abstract: Background— Endothelial dysfunction is a critical intermediate phenotype in the pathogenesis of cardiovascular disease. We evaluated the relative contributions of distinct biological pathways to interindividual variation in endothelial function by relating prototype biomarkers (representing these pathways) to brachial artery vasodilator function. Methods and Results— We investigated the cross-sectional relations of a panel of 7 biomarkers measured at a routine examination to brachial artery vasodilator function (flow-mediated dilation [FMD] and reactive hyperemia) assessed at a subsequent examination (mean interval, 2.9 years) in 2113 Framingham Heart Study participants (mean age, 61 years; 54% women). We selected biomarkers from 4 biological domains: neurohormonal (N-terminal pro-atrial natriuretic peptide [N-ANP], B-type natriuretic peptide [BNP], renin, aldosterone), hemostatic factors (plasminogen activator inhibitor-1 [PAI-1]), inflammation (C-reactive protein [CRP]), and target organ damage (urine a...
88 citations
TL;DR: HIV-infected children with CD4+ T cell percentages > or = 20% responded better to the HAV vaccine if they had undetectable HIV RNA, suggesting that an increase in immunizations may be warranted in this population.
Abstract: aBackground. Human immunodeficiency virus (HIV)‐infected patients have weak responses to vaccines and may require revised immunization regimens. We investigated the safety and immunogenicity of 2 doses of hepatitis A virus (HAV) vaccine followed by a booster dose in HIV-infected children receiving stable highly active antiretroviral therapy. Methods. A total of 235 children with CD4 + T cell percentages 20% received 2 vaccine doses 24 weeks apart, and 117 received a third vaccine dose after 104 weeks. Anti-HAV antibody titers were measured at baseline and at 32, 104, and 112 weeks after the first vaccination. Subjects with antibody titers 20 mIU/mL were defined as being seropositive. High and low antibody responses were defined as titers 250 and !250 mIU/mL, respectively. Results. Of 151 subjects who were HAV seronegative at baseline, 97% seroconverted after 2 vaccine doses, and 47% had low antibody responses. At 104 weeks, 90% of subjects had antibody titers 20 mIU/mL, and those with low antibody responses were more likely to lose protective antibody titers. A third vaccine dose generated significantly higher antibody titers than those observed after the second vaccine dose. Undetectable HIV RNA at baseline was associated with higher anti-HAV antibody titers after the second vaccine dose. Antibody titers after the second and third vaccine doses were weakly correlated with CD4 + T cell percentages at the time when each vaccine dose was administered. In the 45 subjects who were HAV seropositive at baseline, responses to 2 and 3 vaccine doses were higher than those in subjects who were HAV seronegative at baseline, but the responses showed similar correlations. There were no serious adverse events associated with the vaccine. Conclusions. HIV-infected children with CD4 + T cell percentages 20% responded better to the HAV vaccine if they had undetectable HIV RNA. The standard 2-dose immunization regimen generated low antibody titers with limited persistence. A third vaccine dose was safe and increased the antibody titers, suggesting that an increase in immunizations may be warranted in this population. HIV infection causes broad immunosuppression that affects multiple components of the immune system. In addition to having CD4 + T7 cell depletion and decreased cell-mediated immunity, patients with advanced HIV infection have impaired antibody responses to
75 citations
TL;DR: In a large community-based sample, a conservative strategy relating several biomarkers to vascular endothelial function identified plasma N-ANP as a key correlate of mean flow under basal conditions and of FMD in response to forearm cuff occlusion.
Abstract: We thank Drs. Struthers and Lang for their thoughtful comments on the multiple mechanisms that may underlie the association of circulating natriuretic peptides with endothelial function measures. The authors note that natriuretic peptide levels correlate positively with increased vascular stiffness, subclinical myocardial ischemia, and congestive heart failure.1–3 Because the latter 2 conditions are in turn associated with endothelial dysfunction, higher natriuretic peptide levels may …
47 citations
TL;DR: In this paper, the authors evaluated the cross-sectional relations of serum HSP70 to established CVD risk factors (including hypertension), markers of oxidative stress (urinary 8-epi-PGF2α) and inflammation (plasma interleukin-6, C-reactive protein, monocyte chemoattractant protein-1 MCP-1), echocardiographic LV dimensions and prevalent CVD in 456 Framingham Offspring Study participants (mean age 61 years, 42% women).
14 citations
Journal Article•
3 citations