Thrombosis and drug-eluting stents: an objective appraisal

Stent thrombosis (ST) after percutaneous coronary intervention has been the focus of intense interest because of its attendant morbidity and mortality. There is controversy about several facets of the problem. These include the frequency of ST with drug-eluting stents (DES) versus bare-metal stents (BMS), the timing of the event, clinical consequences, risk factors, adjunctive therapy, and new preventive approaches. Information has accrued rapidly from several sources, including randomized controlled clinical trials of DES versus BMS in carefully selected subsets of patients and registry experiences in larger patient groups, which provide a more universal real-world picture. The results from these different data sets are not completely concordant. However, several general conclusions can be made: 1) ST is an infrequent but very severe complication of both BMS and DES; 2) at the present time, during 4 years of follow-up from randomized controlled trials that compared DES and BMS, there is no apparent difference in overall ST frequency, although the time course for occurrence appears to differ, with a relative numeric excess of ST late after DES implant; 3) despite this relative imbalance, no differences in the end points of death or death and infarction between DES and BMS are observed; 4) longer-term follow-up of these patients as well as larger angiographic and clinical subsets of patients who receive this technology outside of randomized trials are required to fully study this issue; and 5) advances in stent platforms for drug elution as well as adjunctive pharmacologic therapy are being evaluated to enhance long-term safety.

Elective implantation of sirolimus-eluting stents for bifurcated and non-bifurcated unprotected left main coronary artery lesions: clinical outcomes at one year

AIMS: Recent studies of drug-eluting stents for unprotected left main coronary artery (LMCA) disease have been encouraging. We examined the performance of sirolimus-eluting stents (SES) for this indication. METHODS AND RESULTS: This retrospective study included 228 consecutive patients (mean age = 68 +/- 11 years, 80.6% men, 26.3% diabetics) who underwent implantation of SES for de novo LMCA stenoses. The mean additive and logistic EuroSCOREs were 5.2 +/- 3.9 and 8.2 +/- 13.2, respectively. The main objective of this study was to measure the rate of major adverse cardiac events (MACE), including death, myocardial infarction and target lesion revascularisation (TLR) at 12 months. Other objectives were to measure the rates of in-hospital MACE and 12-month TLR. Outcomes in 143 patients with (BIF+ group), versus 84 patients without (BIF-group) involvement of the bifurcation were compared. The pre-procedural percent diameter stenosis (%DS) was 60.1 +/- 11.2 in the BIF+ versus 54.7 +/- 12.2% in the BIF- group (p=0.008), and decreased to 18.0 +/- 9.7 and 13.9 +/- 11.3%, respectively (ns), after SES implant. The overall in-hospital MACE rate was 3.5%, and similar in both subgroups. The 1-year MACE rate was 14.5% overall, 16.8% in the BIF+ and 10.7% in the BIF- subgroup (ns). CONCLUSIONS: SES implants in high-risk patients with LMCA stenoses were associated with a low 1-year MACE rate. Stenting of the bifurcation was associated with significant increases in neither mortality nor 1-year MACE rate.

Impact of drug-eluting stent selection on long-term clinical outcomes in patients treated for unprotected left main coronary artery disease: the sirolimus vs paclitaxel drug-eluting stent for left main registry (SP-DELFT)

AIM: To compare the long-term relative efficacy and safety of SES and PES in patients undergoing percutaneous coronary intervention (PCI) for unprotected left main coronary artery (ULMCA) disease and to evaluate the role of lesion location and stenting technique in determining outcomes. METHODS AND RESULTS: From April 2002 to April 2004, 288 consecutive patients who underwent elective PCI with DES implantation for de novo lesions on ULMCA have been retrospectively selected and analyzed in seven European and US tertiary care centers. All patients had a minimum follow-up of 3 years. SES was used in 152 patients while 136 received PES. Isolated ostial-shaft disease was present in 27% of patients. Distal LM disease (73%) was treated with single and double stent approach in 29.5% and 43.4% of patients respectively. After 3 years, rates of survival free from any of the events investigated, were independent from lesion location and stenting approach and did not differ significantly between SES and PES groups. Freedom from MACE (SES vs. PES) was 76.3% vs. 83.1% in the ostial/shaft group, 80.3% vs. 72.8% in the distal-single stent group and 67.1% vs. 66.2% in the distal-double stent group. Definite stent thrombosis occurred only in 1(0.3%) patient at 439 days. CONCLUSIONS: In elective patients who underwent PCI for de novo lesions in the ostium, shaft or distal ULMCA, long-term clinical outcomes with SES and PES use were similar independently of lesion location and stenting technique.

Longest available clinical outcomes after drug-eluting stent implantation for unprotected left main coronary artery disease: the DELFT (Drug Eluting stent for LeFT main) Registry

OBJECTIVES: The purpose of this study was to investigate the long-term safety and efficacy of percutaneous coronary intervention (PCI) with drug-eluting stent (DES) implantation for unprotected left main coronary artery (ULMCA) disease. BACKGROUND: Long-term clinical outcomes after DES implantation for ULMCA disease have not yet been ascertained. METHODS: From April 2002 to April 2004, 358 consecutive patients who underwent PCI with DES implantation for de novo lesions on ULMCA were retrospectively selected and analyzed in 7 European and U.S. tertiary care centers. No patients were excluded from the analysis, and all patients had a minimum follow-up of 3 years. RESULTS: Technical success rate was 100%. Procedural success rate was 89.6%. After 3 years, major adverse cardiovascular events (MACE)-free survival in the whole population was 73.5%. According to the Academic Research Consortium definitions, cardiac death occurred in 9.2% of patients, and reinfarction, target lesion revascularization (TLR), and target vessel revascularization (TVR) occurred in 8.6%, 5.8%, and 14.2% of patients, respectively. Definite stent thrombosis occurred in 2 patients (specifically at 0 and 439 days). In elective patients, the 3-year MACE-free survival was 74.2%, with mortality, reinfarction, TLR, and TVR rates of 6.2%, 8.3%, 6.6%, and 16%, respectively. In the emergent group the 3-year MACE-free survival was 68.2%, with mortality, reinfarction, TLR, and TVR rates of 21.4%, 10%, 2.8%, and 7.1%, respectively. CONCLUSIONS: Routine DES implantation in ULMCA disease seems encouraging, with favorable long-term clinical results.

Diabetic patients treated for unprotected left main coronary artery disease with drug eluting stents: a 3-year clinical outcome study. The diabetes and drug eluting stent for LeFT main registry (D-DELFT)

AIMS: Diabetes mellitus (DM) plays an important role in the development of coronary artery disease. Although previous studies have associated drug-eluting stent (DES) implantation in diabetic patients with favourable clinical and angiographic outcomes, the very long-term efficacy of these devices in diabetic patients undergoing PCI for significant unprotected left main coronary artery (ULMCA) disease has not been established yet. METHODS AND RESULTS: Consecutive diabetic patients (n=100), who underwent elective PCI with DES for de novo lesions in an ULMCA between April 2002 and April 2004 in seven tertiary health care centres, were identified retrospectively and analysed. Consecutive non-diabetic patients (n=193), who underwent elective DES implantation for unprotected ULMCA disease, were selected as a control group. All patients were followed for at least 36 months. At 3-years follow-up, freedom from cardiac death ; myocardial infarction (CDMI), target lesion revascularisation (TLR) and target vessel revascularisation (TVR) did not differ significantly between groups. The adjusted freedom from major adverse cardiac events (MACE, defined as the occurrence of CD, MI or TVR) was 63.4% in the DM group and 77.6% in the controls (p<0.001). When divided into IDDM and NIDDM sub-groups, insulin-dependent DM (IDDM) but not non IDDM (NIDDM) patients had significantly lower freedom from CDMI, TLR, TVR and MACE compared to controls. CONCLUSIONS: These results suggest that major improvements in DES technology and pharmacotherapy are still required to improve clinical outcome and that the decision to perform percutaneous revascularisation in this subset of patients should be taken cautiously and on a case by case basis.

Guidelines for the use and interpretation of assays for monitoring autophagy in higher eukaryotes

Research in autophagy continues to accelerate,(1) and as a result many new scientists are entering the field. Accordingly, it is important to establish a standard set of criteria for monitoring macroautophagy in different organisms. Recent reviews have described the range of assays that have been used for this purpose.(2,3) There are many useful and convenient methods that can be used to monitor macroautophagy in yeast, but relatively few in other model systems, and there is much confusion regarding acceptable methods to measure macroautophagy in higher eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers of autophagosomes versus those that measure flux through the autophagy pathway; thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from fully functional autophagy that includes delivery to, and degradation within, lysosomes (in most higher eukaryotes) or the vacuole (in plants and fungi). Here, we present a set of guidelines for the selection and interpretation of the methods that can be used by investigators who are attempting to examine macroautophagy and related processes, as well as by reviewers who need to provide realistic and reasonable critiques of papers that investigate these processes. This set of guidelines is not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to verify an autophagic response.

The HCP5 single-nucleotide polymorphism: a simple screening tool for prediction of hypersensitivity reaction to abacavir

The HLA-B 5701 allele is predictive of hypersensitivity reaction to abacavir, a response herein termed "ABC-HSR." This study of 1,103 individuals infected with human immunodeficiency virus assessed the usefulness of genotyping a HCP5 single-nucleotide polymorphism (SNP), rs2395029, in relation to ABC-HSR. In populations with European ancestry, rs2395029 is in linkage disequilibrium with HLA-B 5701. The HCP5 SNP was present in all 98 HLA-B 5701-positive individuals and was absent in 999 of 1005 HLA-B 5701-negative individuals. rs2395029 was overrepresented in 25 individuals with clinically likely ABC-HSR, compared with its frequency in 175 ABC-tolerant individuals (80% vs. 2%, respectively; P < .0001). Therefore, HCP5 genotyping could serve as a simple screening tool for ABC-HSR, particularly in settings where sequence-based HLA typing is not available.

In vivo analysis of efavirenz metabolism in individuals with impaired CYP2A6 function

INTRODUCTION: The antiretroviral drug efavirenz (EFV) is extensively metabolized into three primary metabolites: 8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV. There is a wide interindividual variability in EFV plasma exposure, explained to a great extent by cytochrome P450 2B6 (CYP2B6), the main isoenzyme responsible for EFV metabolism and involved in the major metabolic pathway (8-hydroxylation) and to a lesser extent in 7-hydroxylation. When CYP2B6 function is impaired, the relevance of CYP2A6, the main isoenzyme responsible for 7-hydroxylation may increase. We hypothesize that genetic variability in this gene may contribute to the particularly high, unexplained variability in EFV exposure in individuals with limited CYP2B6 function. METHODS: This study characterized CYP2A6 variation (14 alleles) in individuals (N=169) previously characterized for functional variants in CYP2B6 (18 alleles). Plasma concentrations of EFV and its primary metabolites (8-hydroxy-EFV, 7-hydroxy-EFV and N-glucuronide-EFV) were measured in different genetic backgrounds in vivo. RESULTS: The accessory metabolic pathway CYP2A6 has a critical role in limiting drug accumulation in individuals characterized as CYP2B6 slow metabolizers. CONCLUSION: Dual CYP2B6 and CYP2A6 slow metabolism occurs at significant frequency in various human populations, leading to extremely high EFV exposure.

Dental phobia is no contraindication for oral implant therapy

OBJECTIVES Dental phobia is a psychological disease and a possible contraindication for implant therapy. The study aimed to show that implant therapy in dental-phobic patients (DP, test group) after adequate psychological and dental pretreatment (PDPT) is successfully possible and results in a similar implant prognosis as in nonfearful patients (NF, control group). METHOD AND MATERIALS 15 DP with PDPT and 15 NF were treated with dental implants and were re-evaluated 2 to 4 years after denture-mounting regarding: alteration of dental anxiety (Hierarchical Anxiety Questionnaire [HAQ], Visual Analog Scale [VAS]), patient satisfaction and compliance, implant success, and peri-implant health. Statistical tests of non-inferiority DP versus NF were performed with Hodges-Lehmann estimators and respective one-sided 97.5% confidence intervals of Moses, and pairwise testings with Mann-Whitney test. RESULTS The DP test group rated its anxiety significantly lower at follow- up than at baseline (PHAQ < .001). However, at follow-up, anxiety was still higher in DP than in NF (PHAQ = .046; PVAS < .001). Implant success at follow-up was 100%. Oral health was equally good in DP and NF patients. At follow-up, all patients were satisfied with implant therapy, but compliance was better for NF (100%) than for DP (73% dental checkup; 67% dental hygienist). CONCLUSION Implant therapy can be successfully performed in DP patients with PDPT as phobia is not negatively influenced by the invasive implant therapy. However, motivation for professional maintenance programs remains challenging.

Contribution of Genetic Background, Traditional Risk Factors, and HIV-Related Factors to Coronary Artery Disease Events in HIV-Positive Persons

Background Persons infected with human immunodeficiency virus (HIV) have increased rates of coronary artery disease (CAD). The relative contribution of genetic background, HIV-related factors, antiretroviral medications, and traditional risk factors to CAD has not been fully evaluated in the setting of HIV infection. Methods In the general population, 23 common single-nucleotide polymorphisms (SNPs) were shown to be associated with CAD through genome-wide association analysis. Using the Metabochip, we genotyped 1875 HIV-positive, white individuals enrolled in 24 HIV observational studies, including 571 participants with a first CAD event during the 9-year study period and 1304 controls matched on sex and cohort. Results A genetic risk score built from 23 CAD-associated SNPs contributed significantly to CAD (P = 2.9×10−4). In the final multivariable model, participants with an unfavorable genetic background (top genetic score quartile) had a CAD odds ratio (OR) of 1.47 (95% confidence interval [CI], 1.05–2.04). This effect was similar to hypertension (OR = 1.36; 95% CI, 1.06–1.73), hypercholesterolemia (OR = 1.51; 95% CI, 1.16–1.96), diabetes (OR = 1.66; 95% CI, 1.10–2.49), ≥1 year lopinavir exposure (OR = 1.36; 95% CI, 1.06–1.73), and current abacavir treatment (OR = 1.56; 95% CI, 1.17–2.07). The effect of the genetic risk score was additive to the effect of nongenetic CAD risk factors, and did not change after adjustment for family history of CAD. Conclusions In the setting of HIV infection, the effect of an unfavorable genetic background was similar to traditional CAD risk factors and certain adverse antiretroviral exposures. Genetic testing may provide prognostic information complementary to family history of CAD.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals. Homozygous carriers of known CCR5 resistance mutations were excluded. Single nucleotide polymorphisms (SNPs) and inferred copy number variants (CNVs) were tested using logistic regression. In addition, we performed a pathway enrichment analysis, a heritability analysis, and a search for epistatic interactions with CCR5 Δ32 heterozygosity. A total of 560 HIV-uninfected cases were recruited: 36 (6.4%) were homozygous for CCR5 Δ32 or m303. After quality control and SNP imputation, we tested 1 081 435 SNPs and 3686 CNVs for association with HIV-1 serostatus in 431 cases and 765 HIV-infected controls. No SNP or CNV reached genome-wide significance. The additional analyses did not reveal any strong genetic effect. Highly exposed, yet uninfected hemophiliacs form an ideal study group to investigate host resistance factors. Using a genome-wide approach, we did not detect any significant associations between SNPs and HIV-1 susceptibility, indicating that common genetic variants of major effect are unlikely to explain the observed resistance phenotype in this population.

ARMin - robot for rehabilitation of the upper extremities

Task-oriented repetitive movements can improve motor recovery in patients with neurological or orthopaedic lesions. The application of robotics can serve to assist, enhance, evaluate, and document neurological and orthopaedic rehabilitation. ARMin is a new robot for arm therapy applicable to the training of activities of daily living in clinics. ARMin has a semiexoskeletal structure with six degrees of freedom, and is equipped with position and force sensors. The mechanical structure, the actuators and the sensors of the robot are optimized for patient-cooperative control strategies based on impedance and admittance architectures. This paper describes the mechanical structure, the control system, the sensors and actuators, safety aspects and results of a first pilot study with hemiplegic and spinal cord injured subjects.