No abstract

Many recent studies have shown a relationship between plasma C-reactive protein (CRP) concentrations and risk of cardiovascular disease. However, the intraindividual variation in plasma CRP concentrations is large. Use of plasma CRP measurement in individual patients is likely to result in many being misclassi ed in their risk status. Use of repeated measurements is not a practical solution to this problem. 2002; 39: 85-88 In recent years there has been a marked increase in interest in the relationship between C-reactive protein (CRP) and the risk of cardiovascular disease. There are now numerous prospective studies which show that elevated baseline concentrations of CRP are correlated with a higher risk of future cardiovascular morbidity and mortality. 1 The di¡erences in plasma CRP concentrations between una¡ected and a¡ected patient groups in most studies are very small, and often within the reference interval quoted for healthy populations using standard CRP assays. The high-sensitivity CRP (hs-CRP) assays that have been developed to facilitate these studies are quite robust and show good analytical precision. 2 An important factor that has not yet received su¤-cient attention in the literature is the e¡ect of intraindividual variation in plasma CRP concentrations on the utility of the hs-CRP assays in individual patients. The only workers to discuss this have been Macy, Hayes and Russell, 3 who calculated that an individual's plasma CRP would have to change by at least 118% before one could be con¢dent that the change was not just due to intra-individual and analytical variation. They conclude that the usefulness of CRP is limited in detecting early disease-associated changes when used in conjunction with a healthy reference interval. Ann Clin BiochemFigures 1 and 2 from Macy et al. 3 and another recent study 4 show the range of variation in plasma CRP concentrations in individual apparently healthy patients over 6-month periods. Figure 3, from the second study, 4 shows the range of variation in patients with stable angina pectoris over a 5-month period.It is apparent that the intra-individual variation is large. In contrast, the di¡erences between healthy and atherosclerosis risk groups in published prospective studies is small. For example, in the Physician's Health Study Ridker et al.2 found mean plasma CRP concentrations of 1 ¢ 13 mg/L in the men who remained healthy, 1 ¢ 51 mg/L in the men who went on to have a myocardial infarction, and 1¢38 mg/L in the men who went on to have an ischaemic stroke.Inspection of Figs 1 and 2 shows that the majority of apparently healthy subjects will have one or more plasma CRP values over time that would place them in the atherosclerotic risk group. Similarly, inspection of Fig. 3 shows that the majority of the subjects with current angina pectoris will have one or more CRP values over time that place them in the healthy group. A single plasma CRP estimation in an individual subject has a high risk of misclassi¢cation and cannot accurately determine whether...

The theory that lesions formed by retention of circulating LDL can then progress to complicated atherosclerotic lesions has been a subject of debate, as has the mechanism of retention. In earlier work, we identified SAMD1, a protein expressed by intimal smooth muscle cells in human lesions that appears to irreversibly bind apoB-Lps in extracellular matrix near the lumen. We hypothesized this binding could contribute to the formation of lesions in mice, and that inhibiting binding could reduce lesion growth. In mouse models of atherosclerosis, we found that SAMD1 binds LDL; that SAMD1/apoB complex is ingested by intimal cells; and that recognizable epitopes of the SAMD1/apoB complex survive some degree of catabolism in foam cell. These data appear to support the SAMD1/LDL retention hypothesis of lesion growth. Despite apparently irreversible binding of human LDL to full-length human SAMD1, efficient anti-SAMD1-antibody inhibitors were created. In vivo lesion targeting of inhibitors was demonstrated by MRI, ultrasound, and ex vivo microscopy. However, only non-statistically significant reductions in spontaneous lesion size in apoE-/- mice were seen after 12 weeks of treatment with PEG-fab inhibitors of SAMD1/LDL binding. In contrast, inhibitors substantially reduced LDL retention in carotid injury lesions in apoE-/- and LDLR-/- mice 7 days after injury. The most obvious difference between injury lesions and early spontaneous lesions is the presence of numerous SMCs and associated ECM in the injury lesions. Thus, SAMD1 may be involved in retention of apoB-Lps in mouse lesions, but not until smooth muscle cells have entered the intima. In addition, SAMD1 is seen throughout arteries in changing patterns that suggest broader and more complicated roles in atherosclerosis.

No abstract

SAM domain-containing protein 1 (SAMD1) has been implicated in atherosclerosis, as well as in chromatin and transcriptional regulation, suggesting a versatile and complex biological function. However, its role at an organismal level is currently unknown. Here, we generated SAMD1−/− and SAMD1+/− mice to explore the role of SAMD1 during mouse embryogenesis. Homozygous loss of SAMD1 was embryonic lethal, with no living animals seen after embryonic day 18.5. At embryonic day 14.5, organs were degrading and/or incompletely developed, and no functional blood vessels were observed, suggesting failed blood vessel maturation. Sparse red blood cells were scattered and pooled, primarily near the embryo surface. Some embryos had malformed heads and brains at embryonic day 15.5. In vitro, SAMD1 absence impaired neuronal differentiation processes. Heterozygous SAMD1 knockout mice underwent normal embryogenesis and were born alive. Postnatal genotyping showed a reduced ability of these mice to thrive, possibly due to altered steroidogenesis. In summary, the characterization of SAMD1 knockout mice suggests a critical role of SAMD1 during developmental processes in multiple organs and tissues.