Craig Hooper

Vitamin D Status Is Associated With Arterial Stiffness and Vascular Dysfunction in Healthy Humans

OBJECTIVES The primary objective of this study was to elucidate mechanisms underlying the link between vitamin D status and cardiovascular disease by exploring the relationship between 25-hydroxyvitamin D (25-OH D), an established marker of vitamin D status, and vascular function in healthy adults. BACKGROUND Mechanisms underlying vitamin D deficiency-mediated increased risk of cardiovascular disease remain unknown. Vitamin D influences endothelial and smooth muscle cell function, mediates inflammation, and modulates the renin-angiotensin-aldosterone axis. We investigated the relationship between vitamin D status and vascular function in humans, with the hypothesis that vitamin D insufficiency will be associated with increased arterial stiffness and abnormal vascular function. METHODS We measured serum 25-OH D in 554 subjects. Endothelial function was assessed as brachial artery flow-mediated dilation, and microvascular function was assessed as digital reactive hyperemia index. Carotid-femoral pulse wave velocity and radial tonometry-derived central augmentation index and subendocardial viability ratio were measured to assess arterial stiffness. RESULTS Mean 25-OH D was 31.8 ± 14 ng/ml. After adjustment for age, sex, race, body mass index, total cholesterol, low-density lipoprotein, triglycerides, C-reactive protein, and medication use, 25-OH D remained independently associated with flow-mediated vasodilation (β = 0.1, p = 0.03), reactive hyperemia index (β = 0.23, p < 0.001), pulse wave velocity (β = -0.09, p = 0.04), augmentation index (β = -0.11, p = 0.03), and subendocardial viability ratio (β = 0.18, p = 0.001). In 42 subjects with vitamin D insufficiency, normalization of 25-OH D at 6 months was associated with increases in reactive hyperemia index (0.38 ± 0.14, p = 0.009) and subendocardial viability ratio (7.7 ± 3.1, p = 0.04), and a decrease in mean arterial pressure (4.6 ± 2.3 mm Hg, p = 0.02). CONCLUSIONS Vitamin D insufficiency is associated with increased arterial stiffness and endothelial dysfunction in the conductance and resistance blood vessels in humans, irrespective of traditional risk burden. Our findings provide impetus for larger trials to assess the effects of vitamin D therapy in cardiovascular disease.

In non-severe hemophilia A the risk of inhibitor after intensive factor treatment is greater in older patients: A case-control study

Summary.  Background: Twenty‐five percent of new anti‐factor VIII (FVIII) antibodies (inhibitors) that complicate hemophilia A occur in those with mild and moderate disease. Although intensive FVIII treatment has long been considered a risk factor for inhibitor development in those with non‐severe disease, its strength of association and the influence of other factors have remained undefined. Objective: To evaluate risk factors for inhibitor development in patients with non‐severe hemophilia A. Methods: Information on clinical and demographic variables and FVIII genotype was collected on 36 subjects with mild or moderate hemophilia A and an inhibitor and 62 controls also with mild or moderate hemophilia A but without an inhibitor. Results: Treatment with FVIII for six or more consecutive days during the prior year was more strongly associated with inhibitor development in those ≥ 30 years of age compared with those < 30 years of age [adjusted odds ratio (OR) 12.62; 95% confidence interval (CI), 2.76–57.81 vs. OR 2.54; 95% CI, 0.61–10.68]. Having previously received < 50 days of FVIII was also not statistically associated with inhibitor development on univariate or multivariate analysis. Conclusions: These findings suggest that inhibitor development in mild and moderate hemophilia A varies with age, but does not vary significantly with lifetime FVIII exposure days: two features distinct from severe hemophilia A.

Effects of storage-aged red blood cell transfusions on endothelial function in hospitalized patients.

Clinical and animal studies indicate that transfusions of older stored red blood cells (RBCs) impair clinical outcomes as compared to fresh RBC transfusions. It has been suggested that this effect is due to inhibition of nitric oxide (NO)‐mediated vasodilation after transfusion of older RBC units. However, to date this effect has not been identified in human transfusion recipients.

25-hydroxyvitamin D concentration is inversely associated with serum MMP-9 in a cross-sectional study of African American ESRD patients

BackgroundCirculating 25-hydroxyvitamin D [25(OH)D] concentration is inversely associated with peripheral arterial disease and hypertension. Vascular remodeling may play a role in this association, however, data relating vitamin D level to specific remodeling biomarkers among ESRD patients is sparse. We tested whether 25(OH)D concentration is associated with markers of vascular remodeling and inflammation in African American ESRD patients.MethodsWe conducted a cross-sectional study among ESRD patients receiving maintenance hemodialysis within Emory University-affiliated outpatient hemodialysis units. Demographic, clinical and dialysis treatment data were collected via direct patient interview and review of patients records at the time of enrollment, and each patient gave blood samples. Associations between 25(OH)D and biomarker concentrations were estimated in univariate analyses using Pearsons correlation coefficients and in multivariate analyses using linear regression models. 25(OH) D concentration was entered in multivariate linear regression models as a continuous variable and binary variable (<15 ng/ml and ≥15 ng/ml). Adjusted estimate concentrations of biomarkers were compared between 25(OH) D groups using analysis of variance (ANOVA). Finally, results were stratified by vascular access type.ResultsAmong 91 patients, mean (standard deviation) 25(OH)D concentration was 18.8 (9.6) ng/ml, and was low (<15 ng/ml) in 43% of patients. In univariate analyses, low 25(OH) D was associated with lower serum calcium, higher serum phosphorus, and higher LDL concentrations. 25(OH) D concentration was inversely correlated with MMP-9 concentration (r = -0.29, p = 0.004). In multivariate analyses, MMP-9 concentration remained negatively associated with 25(OH) D concentration (P = 0.03) and anti-inflammatory IL-10 concentration positively correlated with 25(OH) D concentration (P = 0.04).ConclusionsPlasma MMP-9 and circulating 25(OH) D concentrations are significantly and inversely associated among ESRD patients. This finding may suggest a potential mechanism by which low circulating 25(OH) D functions as a cardiovascular risk factor.

HTLV-I sequence in lymphoproliferative disorders.

Several recent studies reported the detection of partially deleted HTLV-I provirus in biopsies of lesions from patients with mycosis fungoides (MF) and T-cell anaplastic large-cell lymphoma. We studied lesions from 59 patients (21 B-cell lymphomas: 16 diffuse and five follicular; 11 cutaneous T-cell lymphomas, including seven MF; one T-immunoblastic lymphoma; 10 diffuse anaplastic large-cell lymphomas: two B, four T, and four of indeterminate phenotype; three Hodgkin s lymphomas; eight atypical lymphoid proliferations; four other lymphoid lesions, and one squamous-cell carcinoma) using primers to the gag, pol and pX regions of HTLV-I in the polymerase chain reaction (PCR) to detect relevant sequences. A total of 10 patients showed one or more PCR-amplifiable products, including five of 11 patients with cutaneous T-cell lymphomas (45%) as compared with one of 21 patients with B-cell lymphomas (4.3%). We did not find a high incidence of positivity in anaplastic large-cell lymphomas, as reported previously. Detectable HTLV-I sequences were not limited to any subtype of lymphoma, and a pX sequence was detected in a squamous-cell carcinoma. Sequence analysis of one amplified product from each of the three regions studied showed a 94.2, 100, and 98.9% homology to the corresponding prototypical gag. pol, and pX HTLV-I sequences, respectively, indicating that the amplified sequences were derived from HTLV-I or a very closely related virus. HTLV-I sequences were detected in a significant proportion of patients with cutaneous T-cell lymphoma, but their role in the pathogenesis of the neoplasm is still unclear.

Association between baseline fetal hemoglobin levels and incidence of severe vaso-occlusive pain episodes in children with sickle cell anemia

The ameliorating effect of high fetal hemoglobin (HbF) levels on the incidence of pain episodes in sickle cell anemia (SCA) is well‐known; however, in children this relationship is less clearly established. We hypothesized that higher HbF levels in children with SCA are associated with fewer severe pain episodes. A meta‐analysis of data from the Silent Infarct Transfusion Trial (n = 456) and the Cooperative Study of Sickle Cell Disease (n = 764), demonstrated that baseline HbF levels were associated with the incidence of severe pain, commonly defined across studies as an event requiring hospitalization (P‐value = 0.02). Pediatr Blood Cancer 2013;60:E125–E127.

Phenotypic and genotypic differences in factor XII between African Americans and Caucasians.

1 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1167–73. 2 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516–30. 3 Weitz JI, Middeldorp S, Geerts W, Heit JA. Thrombophilia and new anticoagulant drugs. Hematology (Am Soc Hematol Educ Program) 2004; 424–38. 4 Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166: 729–36. 5 Slooter AJ, Rosendaal FR, Tanis BC, Kemmeren JM, van der Graaf Y, Algra A. Prothrombotic conditions, oral contraceptives, and the risk of ischemic stroke. J Thromb Haemost 2005; 3: 1213–7. 6 Ridker PM,Hennekens CH, LindpaintnerK, StampferMJ, Eisenberg PR,Miletich JP.Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. N Engl J Med 1995; 332: 912–7. 7 Sanson BJ, Friederich PW, Simioni P, Zanardi S, Hilsman MV, Girolami A, ten Cate JW, Prins MH. The risk of abortion and stillbirth in antithrombin-, protein C-, and protein S-deficient women. Thromb Haemost 1996; 75: 387–8. 8 Rey E, Kahn SR, David M, Shrier I. Thrombophilic disorders and fetal loss: a meta-analysis. Lancet 2003; 361: 901–8. 9 Buller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE. Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 401S–28S. 10 Sarasin FP, Bounameaux H. Decision analysis model of prolonged oral anticoagulant treatment in factor V Leiden carriers with first episode of deep vein thrombosis. BMJ 1998; 316: 95–9.

MKL1 C–184>T AND CYP3A5 A–6986>G POLYMORPHISMS ARE ASSOCIATED WITH CONTRAST INDUCED ACUTE KIDNEY INJURY AFTER PCI

Currently, little is known about the relationship between single nucleotide polymorphisms and the risk of contrast induced acute kidney injury (CI–AKI) after PCI. The presence of the MKL1–184 C>T SNP has been associated with atherosclerosis in prior studies. The CYP3A5 gene encodes an enzyme