Osteoprotegerin (OPG) regulates osteoclast and immune functions and appears to represent a protective factor for the vascular system. However, the role of OPG in human atherosclerosis has not been evaluated. In this study, we assessed OPG serum levels in 522 age-matched men who, on the basis of coronary angiography, had either absence of coronary artery disease (CAD) or presence of single-vessel disease, double-vessel disease, or severe triple-vessel disease. OPG serum levels were positively correlated with age (r = 0.28; P < 0.001) and were higher in men with diabetes mellitus (P < 0.01). OPG serum levels in men without CAD were 5.4 +/- 2.0 pmol/liter, compared with 6.1 +/- 2.1 pmol/liter in single-vessel disease (P < 0.005), 5.9 +/- 2.4 in double-vessel disease (P < 0.05), and 6.3 +/- 2.3 pmol/liter in triple-vessel disease (P < 0.001). Moreover, OPG serum levels were positively correlated with the severity of CAD as determined by a CAD scoring system (r = 0.17; P < 0.01). In conclusion, our data underline that OPG serum levels are associated with the severity of CAD and are increased in elderly men and patients with diabetes mellitus. We conclude that increased OPG serum levels may reflect advanced cardiovascular disease in men.

Background/objective: Chest pain is a common complaint and reason for consultation. We aimed to study the epidemiology of chest pain with respect to underlying aetiologies and to establish pre-work-up probabilities for the primary care setting. Methods: We included 1212 consecutive patients with chest pain, aged 35 years and older, attending 74 general practitioners (GPs). GPs recorded symptoms and fi ndings of each patient and provided follow-up information. An independent interdisciplinary reference panel reviewed clinical data of every patient and decided on the aetiology of chest pain at the time of patient recruitment. Results: The prevalence of chest pain among all attending patients was 0.7%. The majority (55.9%) of patients were women. Mean age was 59 (35-93) years. Of these patients, 53.2% had chest pains at the time of consultation and 29.6% presented with acute (Ͻ 48 hours' duration) chest pain. Pain originating from the chest wall was diagnosed in 46.6% of all patients, stable ischaemic heart disease (IHD) in 11.1%, and psychogenic disorders in 9.5%; 3.6% had acute coronary syndrome (ACS). Conclusion:The study adds important information about the epidemiology of chest pain as a frequent reason for consulting primary care practitioners. We provide updated pre-work-up probabilities for IHD for each age and sex category.

Background: Chest pain can be caused by various conditions, with life-threatening cardiac disease being of greatest concern. Prediction scores to rule out coronary artery disease have been developed for use in emergency settings. We developed and validated a simple prediction rule for use in primary care. Methods:We conducted a cross-sectional diagnostic study in 74 primary care practices in Germany. Primary care physicians recruited all consecutive patients who presented with chest pain (n = 1249) and recorded symptoms and findings for each patient (derivation cohort). An independent expert panel reviewed follow-up data obtained at six weeks and six months on symptoms, investigations, hospital admissions and medications to determine the presence or absence of coronary artery disease. Adjusted odds ratios of relevant variables were used to develop a prediction rule. We calculated measures of diagnostic accuracy for different cut-off values for the prediction scores using data derived from another prospective primary care study (validation cohort). Results:The prediction rule contained five determinants (age/sex, known vascular disease, patient assumes pain is of cardiac origin, pain is worse during exercise, and pain is not reproducible by palpation), with the score ranging from 0 to 5 points. The area under the curve (receiver operating characteristic curve) was 0.87 (95% confidence interval [CI] 0.83-0.91) for the derivation cohort and 0.90 (95% CI 0.87-0.93) for the validation cohort. The best overall discrimination was with a cut-off value of 3 (positive result 3-5 points; negative result ≤ 2 points), which had a sensitivity of 87.1% (95% CI 79.9%-94.2%) and a specificity of 80.8% (77.6%-83.9%). Interpretation:The prediction rule for coronary artery disease in primary care proved to be robust in the validation cohort. It can help to rule out coronary artery disease in patients presenting with chest pain in primary care. AbstractPreviously published at www.cmaj.ca @@

Osteoprotegerin (OPG) antagonizes receptor activator of nuclear factor-kappaB ligand (RANKL), the principal regulator of osteoclasts. Of note, OPG-deficient mice display osteoporosis and arterial calcification. Recently, OPG gene polymorphisms have been associated with osteoporosis and early predictors of cardiovascular disease. In this study, we examined OPG gene polymorphisms in 468 men who had absence of coronary artery disease (CAD) or single-, double-, or triple-vessel disease on coronary angiography. Denaturing gradient gel electrophoresis followed by DNA sequencing revealed nucleotide substitutions 149 T-->C, 163 A-->G, 209 G-->A, 245 T-->G, 950 T-->C (all promoter), 1181 G-->C (exon 1), and 6890 A-->C (intron 4), respectively. Although single polymorphisms were not associated with CAD, linkage of polymorphisms 950 and 1181 revealed that haplotypes were overrepresented in men with CAD (chi(2) = 17.05; P = 0.03) with an increased risk of CAD in carriers of genotypes 950 TC/1181 GC and 950 CC/1181 CC (odds ratio, 1.67; 95% confidence interval, 1.02-2.72; P = 0.04). Furthermore, serum OPG levels were correlated with the presence of a C allele at position 950 (P = 0.02). In summary, linkage of genetic variations of the OPG gene at positions 950 and 1181 may confer an increased risk of CAD in Caucasian men.

Deficiency of the cholesteryl ester transfer protein (CETP) in humans is characterized by markedly elevated plasma concentrations of HDL cholesterol and apoA-I. To assess the metabolism of HDL apolipoproteins in CETP deficiency, in vivo apolipoprotein kinetic studies were performed using endogenous and exogenous labeling techniques in two unrelated homozygotes with CETP deficiency, one heterozygote, and four control subjects. All study subjects were administered '3C6-labeled phenylalanine by primed constant infusion for up to 16 h. The fractional synthetic rates (FSRs) of apoA-I in two homozygotes with CETP deficiency (0.135, 0.134 /d) were found to be significantly lower than those in controls (0.196±0.041 /d, P < 0.01).Delayed apoA-I catabolism was confirmed by an exogenous radiotracer study in one CETP-deficient homozygote, in whom the fractional catabolic rate of 125I-apoA-I was 0.139/d (normal 0.216±0.018/d). The FSRs of apoA-II were also significantly lower in the homozygous CETP-deficient subjects (0.104, 0.112/d) than in the controls (0.170±0.023/d, P < 0.01). The production rates of apoA-I and apoA-II were normal in both homozygous CETP-deficient subjects. The turnover of apoA-I and apoA-II was substantially slower in both HDL2 and HDL3 in the CETP-deficient homozygotes than in controls. The kinetics of apoA-I and apoA-II in the CETP-deficient heterozygote were not different from those in controls.These data establish that homozygous CETP deficiency causes markedly delayed catabolism of apoA-I and apoA-II without affecting the production rates of these apolipoproteins. (J.