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Circulating oxidized low-density lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58-year-old men (AIR study) V . S I G U R D A R D O T T I R , B . F A G E R B E R G & J . H U L T H EFrom the Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Göteborg University, Gothenburg, Sweden Abstract. Sigurdardottir V, Fagerberg B, Hulthe J (Sahlgrenska University Hospital, Göteborg University, Gothenburg, Sweden). Circulating oxidized lowdensity lipoprotein (LDL) is associated with risk factors of the metabolic syndrome and LDL size in clinically healthy 58-year-old men (AIR study). J Intern Med 2002; 252: 440-447.Objectives. Hypothetically the atherogenic effect of the metabolic syndrome may be mediated through the increased occurrence of small LDL-particles which are easily modified to atherogenic oxidized LDL (ox-LDL). The aim of this study was to test this concept by examining the association between circulating ox-LDL, LDL-particle size, and the metabolic syndrome. Design and results. A population-based sample of clinically healthy 58-year-old men (n ¼ 391) was recruited. Ox-LDL was measured by ELISA (specific monoclonal antibody, mAb-4E6) and LDL-particle size by gradient gel electrophoresis. The results showed that ox-LDL significantly correlated to factors constituting the metabolic syndrome; triglycerides (r ¼ 0.43), plasma insulin (r ¼ 0.20), body mass index (r ¼ 0.20), waist-to-hip ratio (r ¼ 0.21) and HDL (r ¼ )0.24); (P < 0.001). Ox-LDL correlated also to LDL-particle size (r ¼ )0.42), Apo-B (r ¼ 0.70), LDL (r ¼ 0.65); (P < 0.001) and, furthermore, with Apo A-1 (r ¼ )0.13) and heart rate (r ¼ 0.13); (P < 0.01). Conclusion. The metabolic syndrome was accompanied by high plasma ox-LDL concentrations compared with those without the syndrome. Ox-LDL levels were associated with most of the risk factors constituting the metabolic syndrome and was, in addition related to small LDL-particle size. To our knowledge the present study is the first one to demonstrate that circulating ox-LDL levels are associated with small LDL-particle size in a population representative sample of clinically healthy middle-aged men. The high degree of intercorrelation amongst several factors makes it difficult to clarify the independent role of any specific factor.

BackgroundCytomegalovirus (CMV) is associated with an increased risk of cardiac allograft vasculopathy (CAV), the major limiting factor for long-term survival after heart transplantation (HTx). The purpose of this study was to evaluate the impact of CMV infection during long-term follow-up after HTx.MethodsA retrospective, single-centre study analyzed 226 HTx recipients (mean age 45 ± 13 years, 78 % men) who underwent transplantation between January 1988 and December 2000. The incidence and risk factors for CMV infection during the first year after transplantation were studied. Risk factors for CAV were included in an analyses of CAV-free survival within 10 years post-transplant. The effect of CMV infection on the grade of CAV was analyzed.ResultsSurvival to 10 years post-transplant was higher in patients with no CMV infection (69 %) compared with patients with CMV disease (55 %; p = 0.018) or asymptomatic CMV infection (54 %; p = 0.053). CAV-free survival time was higher in patients with no CMV infection (6.7 years; 95 % CI, 6.0–7.4) compared with CMV disease (4.2 years; CI, 3.2–5.2; p < 0.001) or asymptomatic CMV infection (5.4 years; CI, 4.3–6.4; p = 0.013). In univariate analysis, recipient age, donor age, coronary artery disease (CAD), asymptomatic CMV infection and CMV disease were significantly associated with CAV-free survival. In multivariate regression analysis, CMV disease, asymptomatic CMV infection, CAD and donor age remained independent predictors of CAV-free survival at 10 years post-transplant.ConclusionsCAV-free survival was significantly reduced in patients with CMV disease and asymptomatic CMV infection compared to patients without CMV infection. These findings highlight the importance of close monitoring of CMV viral load and appropriate therapeutic strategies for preventing asymptomatic CMV infection.

Early initiation of everolimus with calcineurin inhibitor therapy has been shown to reduce the progression of cardiac allograft vasculopathy (CAV) in de novo heart transplant recipients. The effect of de novo everolimus therapy and early total elimination of calcineurin inhibitor therapy has, however, not been investigated and is relevant given the morbidity and lack of efficacy of current protocols in preventing CAV. This 12‐month multicenter Scandinavian trial randomized 115 de novo heart transplant recipients to everolimus with complete calcineurin inhibitor elimination 7–11 weeks after HTx or standard cyclosporine immunosuppression. Ninety‐five (83%) patients had matched intravascular ultrasound examinations at baseline and 12 months. Mean (± SD) recipient age was 49.9 ± 13.1 years. The everolimus group (n = 47) demonstrated significantly reduced CAV progression as compared to the calcineurin inhibitor group (n = 48) (ΔMaximal Intimal Thickness 0.03 ± 0.06 and 0.08 ± 0.12 mm, ΔPercent Atheroma Volume 1.3 ± 2.3 and 4.2 ± 5.0%, ΔTotal Atheroma Volume 1.1 ± 19.2 mm3 and 13.8 ± 28.0 mm3 [all p‐values ≤ 0.01]). Everolimus patients also had a significantly greater decline in levels of soluble tumor necrosis factor receptor‐1 as compared to the calcineurin inhibitor group (p = 0.02). These preliminary results suggest that an everolimus‐based CNI‐free can potentially be considered in suitable de novo HTx recipients.

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OBJECTIVE -The aim of this study was to investigate the occurrence of subclinical atherosclerosis and underlying mechanisms in men with newly diagnosed diabetes and established diabetes compared with healthy control subjects. RESEARCH DESIGN AND METHODS-In a population-based study of 61-year-old Caucasian men (n ϭ 271) with established diabetes (n ϭ 50) and newly diagnosed diabetes (n ϭ 24) and healthy control subjects (n ϭ 197), standard risk factors and highly sensitive (hs) C-reactive protein (CRP) were measured. Ultrasound measurements of intima-media thickness (IMT) were performed bilaterally in the common carotid artery, and a composite measure was calculated from common carotid and carotid bulb IMT (composite IMT). The plaque status was assessed.RESULTS -Composite IMT and carotid plaque size increased gradually among the healthy control subjects, newly diagnosed diabetic patients, and established diabetic patients (P for trend Յ0.001, respectively). CRP was higher in newly and established diabetes (NS between diabetes groups) compared with healthy control subjects (P Ͻ 0.001). Total cholesterol levels were lower in newly diagnosed diabetes (5.51 Ϯ 1.13 mmol/l, P Ͻ 0.05) and established diabetes (5.45 Ϯ 1.15 mmol/l, P Ͻ 0.01) compared with those of healthy control subjects (5.77 Ϯ 1.03 mmol/l). In men with diabetes (n ϭ 74), diabetes onset status (newly diagnosed versus established), waist-to-hip ratio (WHR), and serum triglycerides, but not CRP, explained 16% of the variance in composite IMT.CONCLUSIONS -This is the first study to show increased preclinical atherosclerotic changes (IMT and plaque size) and increased inflammation (hs-CRP) in men with newly diagnosed diabetes as well as in patients with established diabetes compared with healthy control subjects. WHR, diabetes onset status (newly diagnosed versus established), and triglycerides, but not CRP, were independent correlates of carotid artery IMT in men with diabetes.

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Background: After heart transplantation (HTx), the interindividual pharmacokinetic variability of immunosuppressive drugs represents a major therapeutic challenge due to the narrow therapeutic window between over-immunosuppression causing toxicity and underimmunosuppression leading to graft rejection. Although genetic polymorphisms have been shown to influence pharmacokinetics of immunosuppressants, data in the context of HTx are scarce. We thus assessed the role of genetic variation in CYP3A4, CYP3A5, POR, NR1I2, and ABCB1 acting jointly in immunosuppressive drug pathways in tacrolimus (TAC) and ciclosporin (CSA) dose requirement in HTx recipients.Methods: Associations between 7 functional genetic variants and blood dose-adjusted trough (C 0 ) concentrations of TAC and CSA at 1, 3, 6, and 12 months after HTx were evaluated in cohorts of 52 and 45 patients, respectively.Results: Compared with CYP3A5 nonexpressors (*3/*3 genotype), CYP3A5 expressors (*1/*3 or *1/*1 genotype) required around 2.2-to 2.6-fold higher daily TAC doses to reach the targeted C 0 concentration at all studied time points (P # 0.003). Additionally, the POR*28 variant carriers showed higher dose-adjusted TAC-C 0 concentrations at all time points resulting in significant differences at 3 (P = 0.025) and 6 months (P = 0.047) after HTx. No significant associations were observed between the genetic variants and the CSA dose requirement.Conclusions: The CYP3A5*3 variant has a major influence on the required TAC dose in HTx recipients, whereas the POR*28 may additionally contribute to the observed variability. These results support the importance of genetic markers in TAC dose optimization after HTx.