Publications

The inducible isoenzyme of nitric oxide synthase (iNOS) generates nitric oxide (NO) in inflammatory diseases such as asthma. The prodrug L-N6-(1-iminoethyl)lysine 5-tetrazole amide (SC-51) is rapidly converted in vivo to the active metabolite L-N6-(1-iminoethyl)lysine (L-NIL). Initially, we performed in vitro experiments in human primary airway epithelial cells to demonstrate that L-NIL causes inhibition of iNOS. In a randomized double-blind placebo-controlled crossover trial, SC-51 was administered as a single oral dose (20 or 200 mg) in separate cohorts of healthy volunteers (two groups of n=12) and mild asthmatic patients (two groups of n=12). SC-51 (200 mg) reduced exhaled breath NO levels to <2 ppb in both healthy volunteers (P<0.001) and mild asthmatics (P<0.001) within 15 min, representing >90% inhibition of baseline levels of NO in asthmatic patients, with the effects lasting at least 72 h. There were no significant effects on blood pressure, pulse rate, or respiratory function (FEV1). This study demonstrates that an inhibitor of iNOS produces marked inhibition of exhaled breath NO in normal and asthmatic subjects without producing the side effects observed following the systemic administration of non-selective NOS inhibitors, and thus provides support for the potential use of iNOS inhibitors to treat a range of inflammatory clinical disorders.

We investigated the relationship between intraprocedural angiographic and echocardiographic AR severity after TAVI, and the clinical robustness of angiographic assessment. Methods and Results: In 74 consecutive patients, the echocardiographic circumferential extent (CE) of the paravalvular regurgitant jet was retrospectively measured and graded based on the VARC-2 cut-points; and angiographic post-TAVI AR was retrospectively quantified using contrast videodensitometry (VD) software that calculates the ratio of the contrast time-density integral in the LV outflow tract to that in the ascending aorta (LVOT-AR). Seventy-four echocardiograms immediately after TAVI were analyzable, while 51 aortograms were analyzable for VD. These 51 echocardiograms and VD were evaluated. Median LVOT-AR across the echocardiographic AR grades was as follows: none-trace, 0.07 (IQR, 0.05-0.11); mild, 0.12 (IQR, 0.09-0.15); and moderate, 0.17 (IQR, 0.15-0.22; P<0.05 for none-trace vs. mild, and mild vs. moderate). LVOT-AR strongly correlated with %CE (r=0.72, P<0.0001). At 1 year, the rate of the composite end-point of all-cause death or HF re-hospitalization was significantly higher in >mild AR patients compared with no-mild AR on intra-procedural echocardiography (41.5% vs. 12.4%, P=0.03) as well as in patients with LVOT-AR >0.17 compared with LVOT-AR ≤0.17 (59.5% vs. 16.6%, P=0.03).VD (LVOT-AR) has good intra-procedural inter-technique consistency and clinical robustness. Greater than mild post-TAVI AR, but not mild post-TAVI AR, is associated with late mortality.

Changes in intracoronary volume reflect the hemodynamic significance of progression or regression of diffuse coronary artery disease where intracoronary catheters cannot be applied for direct measurements due to small vessel dimensions. We have validated the videodensitometric measurement of intracoronary volume with epoxy casts of postmortem human coronary arteries. The volume of 31 coronary segments (cross-sectional areas in a range of 2-13 mm2) measured by fluid-filling using a precision dispenser was compared with the respective single plane intracoronary volume assessments obtained by the videodensitometric algorithm of the new generation Cardiovascular Angiography Analysis System (CAAS II). The true and measured values of volume were compared by calculation of the mean of the signed differences +/- standard deviation and by linear regression analysis. Videodensitometric measurement of intracoronary volume correlate well with fluid-filling of human coronary artery casts (correlation coefficient: r = 0.99, y = 1.96 +/- 0.99x, standard error of estimate: SEE = 3.96) with a significant trend towards overestimation of true volume values (mean difference = 1.73 +/- 3.64 mm3, P < 0.05). Intracoronary volume estimations can be used to measure changes of luminal dimensions of coronary arteries and may offer a new approach to assessment of progression or regression of diffuse coronary artery disease.

Background— This article reports the 2-year clinical, angiographic, and intravascular ultrasound outcomes of the everolimus-eluting stent (EES) compared with the paclitaxel-eluting stent (PES) in the randomized SPIRIT II trial. Methods and Results— This was a prospective, single-blind clinical trial in which a total of 300 patients with de novo native coronary artery lesions were randomized to either EES or PES in a 3:1 fashion. Clinical follow-up was planned at 2 years in all patients. A subset of 152 patients underwent serial angiographic and intravascular ultrasound analyses at 6 months and 2 years. After 2 years, target lesion failure (cardiac death, myocardial infarction, and ischemia-driven target lesion revascularization) rates were 6.6% and 11% in EES and PES, respectively ( P =0.31). At 6 months, a significant reduction in angiographic in-stent late loss and percentage volume obstruction measured by intravascular ultrasound was observed in the EES group. However, at 2-year follow-up, a late increased intimal hyperplasia growth after implantation of an EES was observed. There were no significant differences between EES and PES for in-stent late loss (EES, 0.33�0.37 mm versus PES, 0.34�0.34 mm; P =0.84) and percentage volume obstruction (EES, 5.18�6.22% versus PES, 5.80�6.31%; P =0.65) at 2 years. The incidence of stent thrombosis was low and comparable in both groups (EES, 0.9%; PES, 1.4%). Conclusions— Although the previously reported angiographic and clinical superiority of the EES has vanished over time, this report confirms and extends the previously demonstrated noninferiority in terms of in-stent late loss of the EES when compared with the PES up to 2-year follow-up. There were no significant differences between EES and PES in clinical, angiographic and intravascular ultrasound outcomes at 2 years.

The use of coronary stents decreases the morbidity associated with acute closure and restenosis after balloon angioplasty. Intracoronary ultrasound (ICUS) guidance of stent implantation has been advocated to improve stent deployment and thereby to further improve the clinical outcome after stenting, over and above balloon angioplasty. Whereas the merits of intracoronary ultrasound in this respect still remain to be proven, the present paper illustrates that ICUS itself may also entail complications. This paper repoorts on three cases of stent damage induced or aggravated by the ICUS procedure. Cathet. Cardiovasc. Diagn. 40:265–270, 1997. © 1997 Wiley-Liss, Inc.

Ozone is an oxidizing environmental pollutant that significantly contributes to respiratory health risk. Exposure to increased ambient levels of ozone has been associated to worsening of symptoms of patients with lung diseases like asthma and COPD. In this study we investigate the chronic effects of ozone exposure on Hypoxia Inducible Factor (HIF)-1α binding to Histone Deacetylase (HDAC) 2 and Macrophage Migration Inhibitory Factor (MIF) promoter regions in vivo . C57BL/6J mice were exposed to ozone (2.5 ppm) for 3 hours a day, 2 times a week for a period of 6 weeks. After the last exposure mice were sacrificed for bronchoalveolar lavage (BAL) fluid and lung tissue collections. BAL total cell counts were elevated (predominately macrophages and neutrophils) and was associated with increased levels of cytokines (KC and TNFα) levels in ozone exposed mice indicating the presence of an inflammatory environment in the lung. Lung HIF-1α protein levels were increased in cytoplasm and nuclear fractions of ozone exposed mice compared to normal air exposed mice. Using chromatin immunoprecipitation assays were demonstrate that HIF-1α binds to the promoter regions of both HDAC2 and MIF genes in vivo . This was associated with a reduction in HDAC2 mRNA, protein and activity and an increase in MIF protein and mRNA levels. Ozone-induced HIF-1α protein is able to bind to HDAC2 and MIF promoter regions in vivo identifying these as two novel HIF-1α target genes. Funded by the Wellcome Trust.

Objectives We investigated the impact of sex on outcomes after percutaneous coronary intervention (PCI) with drug-eluting stent (DES). Background Women have a higher risk of adverse outcomes after PCI than do men. However, long-term outcomes of women after contemporary PCI with DES have not been fully investigated. Methods We performed a retrospective cohort study of 4,936 consecutive patients (28.2% women) who underwent PCIs between 2000 and 2004, before and after introduction of DES (bare-metal stent [BMS] group: n = 2,131, DES group: n = 2,805), to assess the impact of sex on long-term PCI outcomes and to compare outcome after PCI of women between the DES and BMS eras. Results Compared with men, women undergoing PCIs were 5 years older and more frequently have comorbidities such as diabetes mellitus and hypertension. In patients treated throughout the BMS and DES eras, there were no differences by sex for risk of all-cause death, myocardial infarction, or target vessel revascularization 3 years after procedure. The procedural complexity was higher in the DES era, nevertheless, risk for target vessel revascularization and major adverse cardiac event at 3 years were significantly lower in women treated with DES than in women treated with BMS (adjusted hazard ratio [HR] for target vessel revascularization: 0.52 [95% confidence interval (CI): 0.36 to 0.75], adjusted HR for major adverse cardiac event: 0.63 [95% CI: 0.48 to 0.83]). Conclusions Although women had worse baseline characteristics, no differences in 3-year outcomes were observed between men and women. Compared with BMS use, DES use has decreased revascularization rate equally in women and men.

Background/Introduction Data on the efficacy and safety of different antiplatelet regimens are limited in patients with increasing total stent length (TSL). Purpose To evaluate the impact of the experimental strategy (1-month dual antiplatelet therapy [DAPT] followed by 23-month ticagrelor monotherapy) vs. the reference regimen (12-month DAPT followed by 12-month aspirin monotherapy) in patients with increasing TSL. Methods The present post-hoc analysis of the Global Leaders trial evaluated the primary endpoint (the composite of the all-cause death and new Q-wave myocardial infarction [MI]) at two years in patients with increasing TSL. In addition, the patient-oriented composite endpoint (POCE) (the composite of all-cause death, any stroke, any MI, and any revascularization) and the net adverse clinical events (NACE) (the composite of POCE and Bleeding Academic Research Consortium [BARC] type 3 or 5 bleeding) were also assessed. Results The cohort of 15,450 patients treated with a biolimus-eluting biodegradable polymer stents were included in this analysis. In the longer TSL group (≥46mm), the experimental strategy significantly reduced the risk of the primary endpoint (3.78% vs. 5.68%, hazard ratio (HR): 0.67, 95% confidence interval (CI): 0.49–0.90, p=0.008, P interaction=0.042) as well as POCE (14.57% vs. 18.11%, HR: 0.79, 95% CI: 0.67–0.92, p=0.003, P interaction=0.010) and NACE (16.07% vs. 19.64%, HR: 0.80, 95% CI: 0.69–0.93, p=0.004, P interaction=0.012) at two years. The risk of BARC type 3 or 5 bleeding at two years was similar between the two antiplatelet regimens. KM in patients with long stenting Conclusion Ticagrelor monotherapy significantly reduced the risk of the primary endpoint, POCE and NACE with a similar risk of BARC type 3 or 5 bleeding at two years in patients with the longer TSL. Acknowledgement/Funding The Global Leaders trial was supported by unrestricted grants from AstraZeneca, Biosensors, and The Medicines Company. ECRI (European Cardiovascular R

Design by GMNIA (Geometrically and Materially Nonlinear Analysis with Imperfections) allows the key behavioural features of structures to be directly captured in the analysis, improving accuracy and dramatically reducing the need for subsequent design checks. Since the analysis of frames typically employs beam elements, in which local buckling of cross-sections cannot be explicitly simulated, cross-section classification and capacity checks remain necessary. However, the step-wise and overly conservative nature of these traditional checks restricts accuracy. To resolve this, the use of strain limits, defined using the Continuous Strength Method, in place of these cross-section checks has been proposed. This design method is extended to indeterminate stainless steel structural systems herein. Ultimate load-carrying capacity predictions from the proposed design approach are compared against results obtained from benchmark shell finite element models as well as predictions using traditional stainless steel design methods. The new design framework allows for element interaction at the cross-section level, the influence of local moment gradients, the partial spread of plasticity, moment redistribution, strain hardening and the visualisation of the structural failure mechanism, resulting in more accurate and consistent resistance predictions. The method is included in AISC 370 and prEN 1993-1-14 offering a step change in efficiency for the future direction of structural stainless steel design.