Long-term fluvastatin reduces the hazardous effect of renal impairment on four-year atherosclerotic outcomes (a LIPS substudy)

peer reviewedMild renal impairment is an important risk factor for late cardiovascular complications. This substudy of the Lescol Intervention Prevention Study (LIPS) assessed the effect of fluvastatin on outcome of patients who had renal dysfunction and those who did not. Complete data for creatinine clearance calculation. (Cockcroft=Gault formula) were available for 1,558 patients (92.9% of the LIPS population). Patients were randomized to fluvastatin or placebo after successful completion of a first percutaneous coronary intervention. Follow-up time was, 3 to 4 years. The effect of baseline creatinine clearance on coronary atherosclerotic events (cardiac death, non-fatal myocardial infarction, and coronary reinterventions not related to restenosis) was evaluated. Baseline creatinine clearance (logarithmic transformation) was inversely associated with an incidence of adverse events among patients who received, placebo. (hazard ratio 0.99, 95% confidence interval 0.982 to 0.998, p = 0.01). However, no association was noted between creatinine clearance and the incidence of adverse events among patients who received fluvastatin (hazard ratio 1.0, 95% confidence interval 0.99 to 1.0, p = 0.63). No further deterioration in creatinine clearance was observed during follow-up; regardless of baseline renal function or allocated treatment. Occurrence of adverse events was not related to changes in renal function during follow-up. Fluvastatin therapy markedly decreased the risk of coronary atherosclerotic events after percutaneous intervention in: patients who had lower values of creatinine clearance at baseline: The benefit of fluvastatin was unrelated to any effect on renal function. (C) 2005 by Excerpta Medica Inc

Physiologic and pathologic functions of the NPP nucleotide pyrophosphatase/phosphodiesterase family focusing on NPP1 in calcification

The catabolism of ATP and other nucleotides participates partly in the important function of nucleotide salvage by activated cells and also in removal or de novo generation of compounds including ATP, ADP, and adenosine that stimulate purinergic signaling. Seven nucleotide pyrophosphatase/phosphodiesterase NPP family members have been identified to date. These isoenzymes, related by up conservation of catalytic domains and certain other modular domains, exert generally non-redundant functions via distinctions in substrates and/or cellular localization. But they share the capacity to hydrolyze phosphodiester or pyrophosphate bonds, though generally acting on distinct substrates that include nucleoside triphosphates, lysophospholipids and choline phosphate esters. PPi generation from nucleoside triphosphates, catalyzed by NPP1 in tissues including cartilage, bone, and artery media smooth muscle cells, supports normal tissue extracellular PPi levels. Balance in PPi generation relative to PPi degradation by pyrophosphatases holds extracellular PPi levels in check. Moreover, physiologic levels of extracellular PPi suppress hydroxyapatite crystal growth, but concurrently providing a reservoir for generation of pro-mineralizing Pi. Extracellular PPi levels must be supported by cells in mineralization-competent tissues to prevent pathologic calcification. This support mechanism becomes dysregulated in aging cartilage, where extracellular PPi excess, mediated in part by upregulated NPP1 expression stimulates calcification. PPi generated by NPP1modulates not only hydroxyapatite crystal growth but also chondrogenesis and expression of the mineralization regulator osteopontin. This review pays particular attention to the role of NPP1-catalyzed PPi generation in the pathogenesis of certain disorders associated with pathologic calcification

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders.

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial

A randomized placebo-controlled study on the effect of nifedipine on coronary endothelial function and plaque formation in patients with coronary artery disease: the ENCORE II study†

Aims Endothelial dysfunction and plaque formation are features of atherosclerosis. Inhibition of L-type calcium channels or HMG-CoA pathway improves endothelial function and reduces plaque size. Thus, we investigated in stable coronary artery disease (CAD) the effects of a calcium antagonist on coronary endothelial function and plaque size. Methods and results In 454 patients undergoing PCI, acetylcholine (10−6 to 10−4 M) was infused in a coronary segment without significant CAD. Changes in coronary diameter were measured and an intravascular ultrasound examination (IVUS) was performed. On top of statin therapy, patients were randomized in a double-blind fashion to placebo or nifedipine GITS 30-60 mg/day and followed for 18-24 months. Blood pressure was lower on nifedipine than on placebo by 5.8/2.1 mmHg (P < 0.001) as was total and LDL cholesterol (4.8 mg/dL; P = 0.495), while HDL was higher (3.6 mg/dL; P = 0.026). In the most constricting segment, nifedipine reduced vasoconstriction to acetylcholine (14.0% vs. placebo 7.7%; P < 0.0088). The percentage change in plaque volume with nifedipine and placebo, respectively, was 1.0 and 1.9%, ns. Conclusion The ENCORE II trial demonstrates in a multi-centre setting that calcium channel blockade with nifedipine for up to 2 years improves coronary endothelial function on top of statin treatment, but did not show an effect of nifedipine on plaque volum

Ablation of the androgen receptor from vascular smooth muscle cells demonstrates a role for testosterone in vascular calcification

Vascular calcification powerfully predicts mortality and morbidity from cardiovascular disease. Men have a greater risk of cardiovascular disease, compared to women of a similar age. These gender disparities suggest an influence of sex hormones. Testosterone is the primary and most well-recognised androgen in men. Therefore, we addressed the hypothesis that exogenous androgen treatment induces vascular calcification. Immunohistochemical analysis revealed expression of androgen receptor (AR) in the calcified media of human femoral artery tissue and calcified human valves. Furthermore, in vitro studies revealed increased phosphate (Pi)-induced mouse vascular smooth muscle cell (VSMC) calcification following either testosterone or dihydrotestosterone (DHT) treatment for 9 days. Testosterone and DHT treatment increased tissue non-specific alkaline phosphatase (Alpl) mRNA expression. Testosterone-induced calcification was blunted in VSMC-specific AR-ablated (SM-ARKO) VSMCs compared to WT. Consistent with these data, SM-ARKO VSMCs showed a reduction in Osterix mRNA expression. However, intriguingly, a counter-intuitive increase in Alpl was observed. These novel data demonstrate that androgens play a role in inducing vascular calcification through the AR. Androgen signalling may represent a novel potential therapeutic target for clinical intervention

SAMHD1-Deficient CD14+ Cells from Individuals with Aicardi-Goutières Syndrome Are Highly Susceptible to HIV-1 Infection

Myeloid blood cells are largely resistant to infection with human immunodeficiency virus type 1 (HIV-1). Recently, it was reported that Vpx from HIV-2/SIVsm facilitates infection of these cells by counteracting the host restriction factor SAMHD1. Here, we independently confirmed that Vpx interacts with SAMHD1 and targets it for ubiquitin-mediated degradation. We found that Vpx-mediated SAMHD1 degradation rendered primary monocytes highly susceptible to HIV-1 infection; Vpx with a T17A mutation, defective for SAMHD1 binding and degradation, did not show this activity. Several single nucleotide polymorphisms in the SAMHD1 gene have been associated with Aicardi-Goutières syndrome (AGS), a very rare and severe autoimmune disease. Primary peripheral blood mononuclear cells (PBMC) from AGS patients homozygous for a nonsense mutation in SAMHD1 (R164X) lacked endogenous SAMHD1 expression and support HIV-1 replication in the absence of exogenous activation. Our results indicate that within PBMC from AGS patients, CD14+ cells were the subpopulation susceptible to HIV-1 infection, whereas cells from healthy donors did not support infection. The monocytic lineage of the infected SAMHD1 -/- cells, in conjunction with mostly undetectable levels of cytokines, chemokines and type I interferon measured prior to infection, indicate that aberrant cellular activation is not the cause for the observed phenotype. Taken together, we propose that SAMHD1 protects primary CD14+ monocytes from HIV-1 infection confirming SAMHD1 as a potent lentiviral restriction factor

Research activity and capability in the European reference network MetabERN

BACKGROUND: MetabERN is one of the 24 European Reference Networks created according to the European Union directive 2011/24/EU on patient's rights in cross border healthcare. MetabERN associates 69 centres in 18 countries, which provide care for patients with Hereditary Metabolic Diseases, and have the mission to reinforce research and provide training for health professionals in this field. MetabERN performed a survey in December 2017 with the aim to produce an overview documenting research activities and potentials within the network. As the centres are multidisciplinary, separated questionnaires were sent to the clinical, university and laboratory teams. Answers were received from 52 out of the 69 centres of the network, covering 16 countries. A descriptive analysis of the information collected is presented. RESULTS: The answers indicate a marked interest of the respondents for research, who expressed high motivation and commitment, and estimated that the conditions to do research in their institution were mostly satisfactory. They are active in research, which according to several indicators, is competitive and satisfies standards of excellence, as well as the education programs offered in the respondent's universities. Research in the centres is primarily performed in genetics, pathophysiology, and epidemiology, and focuses on issues related to diagnosis. Few respondents declared having activity in human and social sciences, including research on patient's quality of life, patient's awareness, or methods for social support. Infrastructures offering services for medical research were rarely known and used by respondents, including national and international biobanking platforms. In contrast, respondents often participate to patient registries, even beyond their specific field of interest. CONCLUSIONS: Taken as a whole, these results provide an encouraging picture of the research capacities and activities in the MetabERN network, which, with respect to the number and representativeness of the investigated centres, gives a comprehensive picture of research on Hereditary Metabolic Diseases in Europe, as well as the priorities for future actions. Marginal activity in human and social sciences points out the limited multidisciplinary constitution of the responding teams with possible consequences on their current capability to participate to patient's empowerment programs and efficiently collaborate with patient's advocacy groups

Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type

Aim To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). Methods and results Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). Conclusion A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957