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Improvement of risk prediction for atherosclerotic cardiovascular disease (ASCVD) is needed. Both ambulatory blood pressure (ABP) and biomarkers amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein and cystatin C improve risk prediction but they have not been evaluated in relation to each other. We analyzed whether NT-proBNP, high-sensitivity C-reactive protein, or cystatin C improved risk prediction beyond traditional ASCVD risk factors combined with 24-hour systolic BP (SBP). Secondary aim was to evaluate whether ABP improved risk prediction when compared with models with the biomarkers. We followed up 907 70-year-old men, free of baseline disease, for incident ASCVD defined as fatal or nonfatal myocardial infarction or fatal or nonfatal stroke for a median of 10 years. Cox regression was used to estimate the association between variables in the models and incident ASCVD. Biomarkers were added to a model containing both traditional risk factors and ABP and the models were compared on C-statistics and net reclassification improvement. Twenty-four hour SBP improved discrimination for incident ASCVD when compared with office SBP in a traditional risk factor model (area under the receiver-operating characteristic curve, +2.4%). NT-proBNP further improved reclassification (+18.7%–19.9%; P<0.01) when added to ABP models, whereas high-sensitivity C-reactive protein and cystatin C did not. Twenty-four hour SBP significantly improved net reclassification when added to a traditional risk factor model that included NT-proBNP. The combination of 24-hour SBP and NT-proBNP improved discrimination and net reclassification for incident ASCVD when compared with office SBP in elderly men. NT-proBNP, but not high-sensitivity C-reactive protein or cystatin C, improved risk prediction and discrimination when added to a model that included ABP. [ABSTRACT FROM AUTHOR]

Objective: To study how Niemann-Pick disease type C1 (NPC1) influences hepatic triacylglycerol (TG) metabolism and to determine whether this is reflected in circulating lipid levels., Methods and Results: In Npc1(-/-) mice, the hepatic cholesterol content is increased but the TG content is decreased. We investigated lipid metabolism in Npc1(-/-) mouse hepatocytes and the association of NPC1 single-nucleotide polymorphisms with circulating TGs in humans. TGs were reduced in Npc1(-/-) mouse serum and hepatocytes. In Npc1(-/-) hepatocytes, the incorporation of [3H]oleic acid and [3H]acetate into TG was decreased, but shunting of oleic acid- or acetate-derived [3H]carbons into cholesterol was increased. Inhibition of cholesterol synthesis normalized TG synthesis, content, and secretion in Npc1(-/-) hepatocytes, suggesting increased hepatic cholesterol neogenesis as a cause for the reduced TG content and secretion. We found a significant association between serum TG levels and 5 common NPC1 single-nucleotide polymorphisms in a cohort of 1053 men, with the lowest P=8.7 x 10(-4) for the single-nucleotide polymorphism rs1429934. The association between the rs1429934 A allele and higher TG levels was replicated in 2 additional cohorts, which included 8041 individuals., Conclusions: This study provides evidence of the following: (1) in mice, loss of NPC1 function reduces hepatocyte TG content and secretion by increasing the metabolic flux of carbons into cholesterol synthesis; and (2) common variation in NPC1 contributes to serum TG levels in humans.

Background: Cardiac troponin I (cTnI), a standard for detection of myocardial damage, has recently been reported to predict acute myocardial infarction or death in patients with unstable coronary heart disease (CHD). Cardiac TnI concentrations increase with age in subjects free from clinical signs of CHD, suggesting silent myocardial damage. We investigated the association between cTnI and future CHD and mortality in a community-based cohort of men., Methods and Results: A community-based study was conducted from August 1991 to May 1995 among 1203 men in Uppsala, Sweden, aged 70 years at baseline with a follow-up of up to 10.4 years with the use of registry data (National Board of Health and Welfare, Sweden). CHD was defined with the use of data taken from the Cause of Death Registry or from first-time hospitalization for CHD as recorded in the Hospital Discharge Registry. Cardiac TnI concentrations were measured blinded for outcome, in frozen baseline plasma samples, with the use of the AccuTnI from Beckman Coulter, Inc. Hazard ratios (HRs) from Cox proportional hazards are presented with 95% confidence intervals (CIs) for a 1-SD increase. In men free from cardiovascular disease (CVD), cTnI predicted death (HR, 1.26; 95% CI, 1.08 to 1.46; P=0.003) or first CHD event (HR, 1.31; 95% CI, 1.11 to 1.54; P=0.001) after adjustment for conventional risk factors: total and HDL cholesterol, plasma glucose, body mass index, smoking, and systolic blood pressure., Conclusions: In this first longitudinal report, cTnI was shown to predict death and first CHD event in men free from CVD at baseline, indicating the importance of silent cardiac damage in the development of CHD and mortality.