A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction

Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acid­induced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5­dihydroxybenzoic acid to a range of 2,5­substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholine­induced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF­2 and H2DCF­DA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RT­PCR and western blotting were utilized to measure Akt, eNOS, Nrf­2, NQO­1 and HO­1 expression. Results: Ex vivo endothelium­dependent relaxation was significantly improved by the glycomimetics under palmitate­induced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitate­induced oxidative stress and enhanced NO production. We demonstrate that the protective effects of pre­incubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROS­induced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease

The ABSORB EXTEND study: preliminary report of the twelve-month clinical outcomes in the first 512 patients enrolled

Aims: The safety and performance of the Absorb Bioresorbable Vascular Scaffold (Absorb BVS) system (Abbott Vascular, Santa Clara, CA, USA) has been previously established in 131 patients from cohort A and cohort B of the first-in-man ABSORB trial. Following this trial, ABSORB EXTEND was initiated as a global continued access study (outside of the USA) to expand experience with the Absorb BVS system to different geographies with broader inclusion criteria to include the treatment of longer lesions and multiple vessels. We report in this manuscript the twelve-month clinical outcomes of the first 512 patients in this population. Methods and results: ABSORB EXTEND is a prospective, single-arm, open-label clinical study which will enrol up to 800 patients at up to 100 sites. Included are patients with lesions <= 28 mm in length and reference vessel diameter of 2.0-3.8 mm (as assessed by on-line QCA or IVUS). Treatment of a maximum of two de novo native coronary artery lesions is permitted when each lesion is located in a different epicardial vessel. An independent clinical events committee adjudicates all endpoint-related events. At one year, for the first 512 patients enrolled in the study, the composite endpoints of ischaemia-driven MACE and ischaemia-driven target vessel failure were 4.3% and 4.9%, respectively. The cumulative rate of ARC defined definite and probable scaffold thrombosis for this population was 0.8% at one year. Conclusions: This interim analysis of the ABSORB EXTEND study shows low rates of MACE and scaffold thrombosis. The study is registered on clinicaltrials.gov (unique identifier NCT01023789)

First case of stenting of a vulnerable plaque in the SECRITT I trial—the dawn of a new era?

Background. a 63-year-old man presented with class II anginal symptoms. Investigations. cardiac catheterization, intravascular ultrasound (IVus) virtual histology, optical coherence tomography and off-line palpography. Diagnosis. the patient was diagnosed as having a culprit lesion in the left circumflex artery and a vulnerable plaque in the left anterior descending artery. Management. the culprit lesion was treated with two overlapping drug-eluting stents. the vulnerable plaque was then treated with a self-expanding stent tailored to shield vulnerable plaques (vProtect (R) Luminal shield). after dilatation of the stent with a low-pressure balloon, IVus and optical coherence tomography showed excellent apposition of the stent to the vessel wall, with no signs of tissue prolapse or edge dissections. at the 6-month follow-up appointment, the stent showed complete tissue coverage without signs of in-stent restenosis. Conclusions. six months of follow-up has demonstrated that a patient with an IVUS-derived, thin capped fibroatheroma was successfully treated with a stent tailored to shield vulnerable plaques

Bacterial and host determinants of cough aerosol culture positivity in patients with drug-resistant versus drug-susceptible tuberculosis

A burgeoning epidemic of drug-resistant tuberculosis threatens to derail global control efforts. Although the mechanisms remain poorly clarified, drug-resistant strains are widely believed to be less infectious than drug-susceptible strains. Consequently, we hypothesised that lower proportions of drug-resistant TB patients would have culturable Mycobacterium tuberculosis from respirable cough-generated aerosols compared to drug-susceptible TB patients, and that multiple factors, including mycobacterial genomic variation, would predict culturable cough aerosol production. We enumerated colony forming units (CFU) in aerosols (≤10μm) from 500 tuberculosis patients (227 with drug-resistance), compared clinical characteristics, and performed mycobacterial whole genome sequencing, dormancy phenotyping, and drug susceptibility analyses on M. tuberculosis from sputum. After considering treatment duration, we found that almost half of drug-resistant tuberculosis patients were cough aerosol culture-positive. Surprisingly, neither mycobacterial genomic variants, lineage, nor dormancy status predicted cough aerosol culture-positivity. However, mycobacterial sputum bacillary load and clinical characteristics, including a lower symptom score and stronger cough, were strongly predictive; thereby supporting targeted transmission-limiting interventions. Effective treatment largely abrogated cough aerosol culture-positivity, however, this was not always rapid. These data question current paradigms, inform public health strategies, and suggest the need to redirect tuberculosis transmission-associated research efforts towards host-pathogen interactions