Impact of the metabolic syndrome on the clinical outcomes of non-clinically diagnosed diabetic patients with acute coronary syndrome

The aim of this study is to explore the impact of metabolic syndrome (MS) on the outcome of patients with non-clinically diagnosed diabetes with acute coronary syndrome (ACS) based on a comprehensive nationwide registry during a 1-year follow-up. In the ACS Israeli Survey, 1,060 consecutive patients with non-clinically diagnosed diabetes were admitted due to ACS; 359 patients with MS features on admission were compared with 701 subjects without MS. A modified National Cholesterol Education Program Adult Treatment Panel III definition of MS was used in patients who presented with > or =3 of the 5 components: (1) hyperglycemia, defined as occasional blood glucose on admission >140 mg/dl; (2) preexisting hypertension; (3) body mass index >28 kg/m(2); (4) high-density lipoprotein cholesterol < or =40 mg/dl (men) or < or =50 mg/dl (women); and (5) triglycerides > or =150 mg/dl. Patients with MS were more frequently women (27% vs 12%, p = 0.001), were in Killip > or =II on admission (19% vs 14%, p = 0.03), and had higher 30-day (5.0% vs 1.7%, p = 0.002) and 1-year (8.9% vs 4.6%, p = 0.005) crude mortality rates. Patients with hyperglycemia (glucose >140 mg/dl) and MS had higher 30-day mortality rates compared with patients with hyperglycemia without MS (8.3% vs 2.5%, p <0.05). Multivariate analysis identified MS as a strong independent predictor of 30-day and 1-year mortality with hazard ratios of 2.54 (95% confidence interval 1.22 to 5.31) and 1.96 (95% confidence interval 1.18 to 3.24), respectively. In conclusion, MS defined early at admission is a strong independent predictor of mortality and morbidity in patients with non-clinically diagnosed diabetes with ACS.     

F8 gene dosage defects in atypical patients with severe haemophilia A

Summary. We performed molecular analysis of the factor 8 gene (F8) in 272 unrelated Spanish patients with haemophilia A (HA) and detected a mutation by routine analysis in 267 of them (98.1%). No mutation was detected in the remaining five patients despite clinical and laboratory confirmation of HA. The aim is to describe the molecular alterations in F8 discovered by gene dosage methodologies in three of these patients. For methodology, F8 sequencing, intragenic marker analysis, multiplex ligation-dependent probe amplification and quantitative real time-PCR were followed. One patient had Klinefelter syndrome (47,XXY) and a large deletion spanning exons 1-12 masked by the other F8 allele; the second patient showed a large duplication spanning exons 2-10 and the third patient revealed a non-contiguous double duplication of exons 14 and 23-25. The remaining two patients had mild HA and dosage results were normal. The application of gene dosage methods is useful to define haemophilic patients in whom mutations are not detected using other routine methods. Nevertheless, in a small percentage of patients (<1%), no molecular pathology can be identified after testing several genetic methodologies.     

Autoantibodies to oxidized low-density lipoprotein in coronary artery disease

BACKGROUND: The significance of antioxidized low-density lipoprotein (oxLDL) antibodies in atherogenesis is not yet clear, and there are conflicting data regarding anti-oxLDL levels in early hypertension. METHODS: The levels of anti-oxLDL antibodies were studied in coronary artery disease patients with (n = 82) or without (n = 36) hypertension, in association to other risk factors for coronary artery disease. RESULTS: The levels of anti-oxLDL antibodies did not differ significantly between coronary artery disease patients with or without hypertension. (0.132 +/- 0.146 v 0.153 +/- 0.158 optical density at 405 nm, respectively; P = .48). No significant differences in anti-oxLDL antibodies were found between men and women with and without hypertension, between hypertensive patients with normal and abnormal blood pressure measurements, and between medicated and nonmedicated hypertensive patients. The presence of diabetes mellitus, smoking, and hypercholesterolemia, either solely or in combination, did not result in significant differences in antibody levels in the hypertensive or normotensive patients. CONCLUSIONS: Although the levels of oxLDL antibodies might be modified in early hypertension, once advanced coronary artery disease has developed the presence of hypertension does not affect anti-oxLDL levels.     

Shear stress is required for the endocytic uptake of the factor VIII‐von Willebrand factor complex by macrophages

Summary. Background: Low‐density lipoprotein (LDL) receptor family members contribute to the cellular uptake of factor VIII. How von Willebrand factor fits into this endocytic pathway has remained poorly understood. Objectives: It has been suggested that macrophages contribute to the clearance of the factor VIII (FVIII)‐von Willebrand factor (VWF) complex. We now assessed the mechanisms of uptake employing human monocyte‐derived macrophages. Methods: A confocal microscopy study was employed to study the uptake by monocyte‐derived macrophages of a functional green fluorescent FVIII‐GFP derivative in the presence and absence of VWF. Results: The results revealed that FVIII‐GFP is internalized by macrophages. We found that FVIII‐GFP co‐localizes with LDL receptor‐related protein (LRP), and that the LRP antagonist Receptor Associated Protein (RAP) blocks the uptake of FVIII‐GFP. However, FVIII‐GFP was not detected in the macrophages in the presence of VWF, suggesting that the FVIII‐VWF complex is not internalized by these cells at all. Apart from static conditions, we also investigated the effect of shear stress on the uptake of FVIII‐GFP in presence of VWF. Immunofluorescence studies demonstrated that VWF does not block endocytosis of FVIII‐GFP under flow conditions. Moreover, VWF itself was also internalized by the macrophages. Strikingly, in the presence of RAP, endocytosis of FVIII‐GFP and VWF was inhibited. Conclusion: The results show that shear stress is required for macrophages to internalize both constituents of the FVIII‐VWF complex.     

Long-term diuretic therapy in patients with coronary disease: increased colon cancer-related mortality over a 5-year follow-up.

OBJECTIVES: Recent studies have suggested that long-term diuretic therapy may be associated with increased risk of renal cell carcinoma. This carcinoma is not a common malignancy, but it shares risk factors with the considerably more widespread colon cancer (CC). However, there are no data whether or not a relationship between long-term diuretic therapy and CC mortality exists. In this study we tested the hypothesis that long-term diuretic therapy may be associated with increased CC mortality over a 5.6-year follow-up period. SUBJECTS AND METHODS: The study sample comprised 14 166 patients aged 45 to 74 years with a previous myocardial infarction and/or stable anginal syndrome, screened for participation in the bezafibrate infarction prevention (BIP) study. There were 2153 patients receiving diuretics and 12 013 patients receiving no diuretics. RESULTS: During the follow-up 139 (6.5%) new cases of cancer were diagnosed in the diuretic-treated group compared with 622 (5.2%) in the group receiving no diuretics (P = 0.02). Colon cancer mortality was significantly higher in the diuretic-treated patients (0.1 vs 0.5%, P = 0.001), whereas mortality differences for other cancer types were not documented. Multivariate analysis identified diuretics as an independent predictor of increased colon cancer incidence and colon cancer mortality with a hazard ratio (HR) of 2.0 (95% CI 1.2-3.2) for colon cancer incidence and 3.7 (95% CI 1.7-8.3) for mortality. However, the association between diuretic therapy and higher incidence of colon cancer was observed only among non-users of aspirin. A relatively lower colon cancer incidence was observed in the furosemide subgroup, and higher in the small combined amiloride/hydrochlorthiazide subgroup (HR 3.15, 95% CI 1.15-8.65). CONCLUSION: Long-term exposure to diuretic therapy may be associated with an increased colon cancer-related mortality.     

Does participation in a long-term clinical trial lead to survival gain for patients with coronary artery disease?

PURPOSE: Little is known about the advantages and disadvantages of participation in a clinical trial for patients with coronary heart disease. We hypothesized that participation itself in a long-term clinical trial with regular clinical evaluation and adjustment of treatments might lead to survival gain among patients with coronary artery disease who agreed or refused to participate in the Bezafibrate Infarction Prevention study. SUBJECTS AND METHODS: The study was performed in 18 university hospitals. There were 3502 patients who fulfilled the inclusion criteria. Among them, 3122 patients signed informed consent and were included in the study ("participants"), whereas 380 declined to participate ("nonparticipants"). For all participants, routine visits to the clinics were scheduled bimonthly for study medication distribution and compliance assessment, and every 4 months for clinical evaluation and management. Nonparticipants continued with community-based treatment and were followed only for mortality. RESULTS: The two groups were similar with regard to age, sex, and the prevalence of most cardiovascular diseases, risk factors, and medications, except that participants were more likely to have presented with an anginal syndrome (1788 [57%] vs. 190 [50%]) and to have symptomatic heart failure (754 [25%] vs. 66 [18%]). During follow-up (mean [+/- SD], 7.7 +/- 0.8 years), 475 patients died. All-cause mortality was similar in participants (n = 423 [13.6%]) and nonparticipants (n = 52 [13.7%]). In a multivariate analysis, participation in the clinical trial was not associated with all-cause mortality (hazard ratio [HR] = 0.96; 95% confidence interval [CI]: 0.70 to 1.30) or cardiac mortality (HR = 1.12; 95% CI: 0.72 to 1.74). CONCLUSION: Participation in a long-term clinical trial in a country with readily accessible community-based medicine may not lead to survival gain in patients with coronary artery disease.