Decreased levels of stem cell factor in subjects with incident coronary events.

BACKGROUND: It has been proposed that vascular progenitor cells play an important role in vascular repair, but their possible clinical importance in cardiovascular disease has not been fully characterized. Vascular endothelial growth factor A, placental growth factor and stem cell factor (SCF) are three growth factors that are important in recruiting vascular progenitor cells. In this study, we investigated the association between the plasma levels of these growth factors and incident coronary events (CEs). METHODS: Levels of the three growth factors were measured using the proximity extension assay technique in baseline plasma samples from 384 subjects with a first CE (mean follow-up 14.0 ± 4.3 years) and 409 event-free control subjects matched by sex and age, as well as in homogenates from 201 endarterectomy specimens. RESULTS: After controlling for known cardiovascular disease risk factors in a Cox regression model, subjects in the lowest SCF tertile had a hazard ratio of 1.70 (95% confidence interval 1.14-2.54) compared with subjects in the highest SCF tertile. Lower SCF levels were also associated with more severe carotid disease, less fibrous atherosclerotic plaques and an increased incidence of heart failure. Expression of the SCF receptor c-kit was demonstrated in the subendothelial layer and fibrous cap of human atherosclerotic plaques. Smokers and subjects with diabetes had decreased levels of SCF compared with control subjects. CONCLUSION: To our knowledge, this is the first clinical study to provide evidence to support a key role for SCF and progenitor cells in vascular repair. We suggest that the SCF-c-kit pathway may be a promising biomarker and therapeutic target in cardiovascular disease.

Plasma oxidized LDL: a predictor for acute myocardial infarction?

OBJECTIVES: Oxidized LDL has been attributed a key role in the development of atherosclerosis. Previous studies have demonstrated increased plasma levels of oxidized LDL in patients with established coronary artery disease. The aim of the present study was to investigate if plasma oxidized LDL also predicts risk for development of coronary heart disease (CHD). DESIGN: We used a nested case-control design to study the association between plasma levels of oxidized LDL and risk for development of acute myocardial infarction (AMI) and/or death by CHD. SUBJECTS: Oxidized LDL was analysed by ELISA in cases (n = 26), controls (n = 26) and controls with LDL cholesterol >5.0 mmol L-1 (n = 26). RESULTS: Oxidized LDL correlated with total plasma and LDL cholesterol in both cases (r = 0.72, P < 0.01, r = 0.69, P < 0.01, respectively) and controls (r = 0.71, P < 0.01, r = 0.77, P < 0.01, respectively). The oxidized LDL/plasma cholesterol ratio was higher amongst cases (13.5, range 10.7-19.8) than in controls (12.6, range 9.5-15.8, P < 0.05) and hypercholesterolaemic controls (12.2, range 8.0-16.0, P < 0.01). CONCLUSIONS: These findings identify high plasma oxidized LDL/total cholesterol ratio as a possible indicator of increased risk for AMI.

DNA analysis in a MHC heterozygous patient with complete C4 deficiency--homozygosity for C4 gene deletion and C4 pseudogene.

Virtually all cases of inherited C4 deficiency appear to be caused by homozygosity for rare MHC haplotypes carrying combined defects of genes coding for the C4A and C4B isotypes. The present analysis concerned a C4-deficient patient with two different MHC haplotypes, [HLA-A2, B40, SC00, DR6] and [HLA-A30, B18, F1C00, DR3]. Digestion of genomic DNA from the patient with Taq I and probing with a 5' cDNA C4 probe and a CYP21-specific probe gave only a 7.0-kb and a 3.7-kb band, respectively. The analysis of restriction fragment length polymorphism in family members showed that both C4-deficient haplotypes contained a C4 pseudogene at the C4 locus I and a CYP21 gene together with a deletion of the C4B gene and the adjacent CYP21P gene. None of the C4 pseudogenes contained C4A- or C4B-specific nucleotide sequences as judged from hybridization studies of polymerase chain reaction products. The findings illustrate the high degree of polymorphism in C4 genes and that both gene deletions and presence of a C4 pseudogene are common as reasons for C4 null alleles. The rare C4 double null alleles appear to have arisen in different MHC haplotypes independently.