Publications

The TAXUS(R) database was used to perform an integrated analysis across several large phase II and III trials to assess outcomes of polymer-based paclitaxel-eluting TAXUS stents in diabetic patients.While drug-eluting stents have reduced the risk for restenosis, diabetic patients remain at higher risk.This post hoc analysis of clinical and angiographic outcomes combined individual patient data from four randomized, multicentre, controlled clinical trials (TAXUS II, IV, V, and VI) representing outcomes across two paclitaxel release formulations and stent platforms.Breslow-Day analysis indicated homogeneous odds ratios across dose formulations and stent platforms, thus clinical data (9 months) were pooled from 3445 patients, including 814 diabetic patients. The randomized quantitative coronary angiography subset (n=2863) included 469 diabetic patients requiring oral medications only and 216 insulin-treated. Among patients receiving bare metal stents (BMS), those with diabetes had worse clinical and angiographic outcomes than non-diabetic patients. Target lesion revascularization rates were decreased in TAXUS patients relative to BMS controls by 59% (p=0.0001) among diabetic patients requiring oral medications, by 66% (p=0.006) among insulin-treated. Insulin-treated patients showed a significant TAXUS benefit for in-stent and in-segment percent diameter stenosis (p=0.0001, p=0.001, respectively) and late loss (p=0.001); a similar TAXUS benefit was seen in diabetic patients treated with oral medications (p<0.0001). Binary restenosis in-segment was significantly decreased 65% in both diabetic subsets (p=0.0001).This post hoc analysis of data from four combined randomized TAXUS trials suggests the TAXUS benefit observed in non-diabetic patients is carried over into the high-risk diabetic population.

No abstract is provided for this article.

Cough is a common and protective reflex, but persistent coughing is debilitating and impairs quality of life. Antitussive treatment using opioids is limited by unacceptable side effects, and there is a great need for more effective remedies. The present study demonstrates that theobromine, a methylxanthine derivative present in cocoa, effectively inhibits citric acid-induced cough in guinea-pigs in vivo. Furthermore, in a randomized, double-blind, placebo-controlled study in man, theobromine suppresses capsaicin-induced cough with no adverse effects. We also demonstrate that theobromine directly inhibits capsaicin-induced sensory nerve depolarization of guinea-pig and human vagus nerve suggestive of an inhibitory effect on afferent nerve activation. These data indicate the actions of theobromine appear to be peripherally mediated. We conclude theobromine is a novel and promising treatment, which may form the basis for a new class of antitussive drugs.

Background— Computed tomography–adapted Leaman score (CT-LeSc) was developed to quantify coronary CT angiography information about atherosclerotic burden (lesion localization, stenosis degree, and plaque composition). The objective of the study is to evaluate CT-LeSc long-term prognostic value in patients with suspected coronary artery disease (CAD). Methods and Results— Single-center prospective registry including 1304 consecutive patients undergoing coronary CT angiography for suspected CAD. High CT-LeSc was defined by upper tertile (score, &gt;5) cutoff. Segment involvement score and segment stenosis score were also evaluated. Hard cardiac events (cardiac death and nonfatal acute coronary syndromes) were considered for analysis. Different Cox regression models were used to identify independent event predictors. Kaplan–Meier event-free survival was evaluated in 4 patient subgroups stratified by obstructive (≥50% stenosis) versus nonobstructive CAD and a high (&gt;5) versus a low (≤5) CT-LeSc. Of 1196 patients included in the final analysis (mean follow-up of 52±22 months), 125 patients experienced 136 hard events (18 cardiac deaths and 118 nonfatal myocardial infarction). All atherosclerotic burden scores were independent predictors of cardiac events (hazard ratios of 3.09 for segment involvement score, 4.42 for segment stenosis score, and 5.39 for CT-LeSc). Cumulative event-free survival was 76.8% with a high CT-LeSc and 96.0% with a low CT-LeSc. Event-free survival in nonobstructive CAD with high CT-LeSc (78.6%) was similar to obstructive CAD with high CT-LeSc (76.5%) but lower than obstructive CAD with low CT-LeSc (80.7%). Conclusions— CT-LeSc is an independent long-term predictor of hard cardiac events. Patients with nonobstructive CAD and high CT-LeSc had hard event-free survival similar to patients with obstructive CAD.

Introduction: We have recently found that impaired protein tyrosine phosphatase PTPRR and serine/threonine phosphatase PP2A expression and activity lead to lower dephosphorylation of glucocorticoid receptor (GR)-Ser 226 via c-Jun N-terminal kinase 1 (JNK1), and to lower nuclear translocation of GR, resulting in corticosteroid insensitivity. Aims: To elucidate the association between PTPRR and PP2A in regulation of corticosteroid sensitivity. Methods: Protein expression of PTPRR and PP2A catalytic subunit (PP2A C ) and phosphorylation levels of PP2A C -Tyr 307 were evaluated by Western-Blot in monocytic U937 cell line or peripheral blood mononuclear cells (PBMCs). Effects of PTPRR and PP2A knock down using siRNA were evaluated in U937 cells. Phosphatase activities of immunopurified PTPRR and PP2A C were analyzed by fluorescence-based assay. Results: In PBMCs from severe asthmatics, PTPRR and PP2A C expression were reduced and positively correlated to each other. PTPRR was associated with PP2A C in the cytoplasm. PTPRR reduction attenuated PP2A C expression and activity with concomitant enhancement of PP2A C -Tyr 307 phosphorylation whereas PP2A reduction did not alter PTPRR expression or activity. In addition, PTPRR expression positively correlated with PP2A C -Tyr 307 phosphorylation and negatively with PP2A C activity. Interestingly, PTPRR was activated by formoterol, independently of β 2 adrenoceptor. Conclusion: We have demonstrated that reduction of PTPRR down-regulates PP2A C via enhancement of PP2A C -Tyr 307 phosphorylation that may lead to corticosteroid insensitivity. This novel mechanism may be a new therapeutic target for restoration of corticosteroid sensitivity in patients with severe asthma.

Background The complex interplay between Coronary Microvascular Dysfunction (CMD) and ST-segment Elevation Myocardial Infarction (STEMI) presents significant clinical hurdles. CMD, commonly seen as a complication following STEMI, is associated with adverse cardiovascular outcomes and persistent anginal symptoms. Despite its clinical relevance, the link between CMD post-STEMI and subsequent left ventricular (LV) diastolic dysfunction, along with functional LV remodelling (FLVR), is yet to be fully explored. Purpose Examine the link between CMD 3 months post-STEMI and its impact on FLVR and diastolic dysfunction. Methods This prospective, observational cohort study focused on STEMI patients. At 3-month post-STEMI, a comprehensive coronary physiology assessment of the culprit artery was conducted using the thermodilution method to measure fractional flow reserve (FFR), coronary flow reserve (CFR), and the index of microcirculatory resistance (IMR). CMD was identified with an IMR ≥ 25 or a CFR &amp;lt; 2.0, assuming an FFR &amp;gt; 0.80. Diastolic dysfunction was classified according to ASE/EACVI 2016 guidelines. FLVR was categorized as per Surenjav Chimed et al.'s criteria: Group I with no significant changes in LV size or function, Group II with a decrease in LV ejection fraction (LVEF) greater than 5% without LV dilatation, Group III with an increase in left ventricular end-diastolic volume (LVEDV) ≥ 20%, and Group IV showing both an increase in LVEDV ≥ 20% and a decrease in LVEF over 5%. The study aimed to elucidate the relationship between CMD and the progression of FLVR and diastolic dysfunction, tracked over a 12-month period. Results The study involved 210 patients, mostly men (59.5%), with a median age of 65 (IQR: 58–76). At the 3-month follow-up, CMD was observed in 57 (27.1%) patients. CMD patients had a higher female prevalence (63.2% vs. 32.0%; p &amp;lt; 0.001) and more diabetes (42.1% vs. 17.7%; p &amp;lt; 0.001) compared to non-CMD patients. Both groups shared similar body mass indices, medications, and other risk factors. Laboratory results were similar between groups, except brain natriuretic peptide levels were higher in CMD patients (70.0 vs. 37.0 ng/L; p &amp;lt; 0.001). After 12 months, CMD patients demonstrated significantly less recovery in LVEF (-10.00% vs. 8.00%; p &amp;lt; 0.001), higher prevalence of grade 2 LV diastolic dysfunction (73.08% vs. 1.32%; p &amp;lt; 0.001), and a higher incidence of advanced FLVR (notably in Groups 3 and 4) compared to non-CMD (11.32% vs. 7.28% and 22.64% vs. 1.99%, respectively; p &amp;lt; 0.001). In the adjusted multivariable logistic regression analysis, IMR values independently predicted more severe FLVR and diastolic dysfunction. Conclusions This study highlights that CMD 3 months after STEMI is linked to worse FLVR, diastolic dysfunction, and less recovery in LVEF, emphasizing the need for early CMD detection for better risk assessment. Further research is essential to explore underlying mechanisms and intervention opportunities.LVEF Changes at 12 Months by CMD StatusDiastolic Dysfunction and LV Remodeling

Rationale: COPD is characterized by chronic pulmonary inflammation associated with release of inflammatory mediators including IL-1β, CXCL8 and IL-6, which sustain the inflammatory process and lead to tissue damage. IRAK-4 (interleukin-1 receptor-associated kinase 4), mediates the innate immune response downstream of activation of IL-1β and toll-like receptors, hence inhibition of this pathway may be anti-inflammatory. This study investigated the effect of IRAK4 inhibitors on chemokine production from human bronchial epithelial cells. Methods: Beas-2B and primary human bronchial epithelial cells (HBEC) were pre-treated with IRAK4 inhibitors PFE1-3 or dexamethasone (DEX) prior to stimulation with IL1-β. After 24h, cytokines were measured by ELISA. Results: IRAK4 inhibitors attenuated IL-1[beta-stimulated] release of CXCL8 and IL-6 from both Beas-2B and HBEC. IRAK4 inhibitors were more potent than DEX (Table 1) and this effect was more prominent in HBEC with respect to IL-6 release. Conclusions : IRAK4 inhibition attenuates inflammatory cytokine release from epithelial cells and may be a novel therapeutic strategy for inflammatory lung diseases.

In the last two decades, several studies and widespread clinical use demonstrated that coronary computed tomography angiography (CCTA) is an appropriate method for the non-invasive assessment of patients with suspected stable coronary artery disease (CAD) and low-to-intermediate pretest likelihood of CAD. Moreover, a growing body of literature is showing that CCTA may have also a clinical role in patients with high pretest likelihood of CAD, known CAD and complex and diffuse disease. Particularly, the SYNTAX II trial demonstrated the feasibility of planning interventional and surgical coronary procedures with CCTA thanks to its ability to combine, in a single method, precise stenosis quantification, accurate plaque characterization, functional assessment with fractional flow reserve derived from standard acquired CCTA datasets, and selection of the revascularization modality for any individual patient and of the vessels that need to be revascularized. More recently, the SYNTAX III Revolution trial showed, in patients with three-vessel CAD with or without left main involvement, that treatment decision-making between percutaneous coronary intervention and coronary artery bypass grafting based on CCTA only has an almost perfect agreement with the treatment decision derived from invasive coronary angiography (ICA). The high degree of correlation between CCTA and ICA suggests the potential feasibility of treatment decision-making based solely on non-invasive imaging and clinical information. New research prospects have opened up for the future to demonstrate the true feasibility and safety of this innovative approach in the clinical arena.

Introduction: The prevalence of abdominal aortic aneurysms(AAA) is at least twice as high in patients with coronary artery disease(CAD), and about half of the AAA-patients have clinically relevant CAD. Detecting concomitant disease and intervening on pathophysiological mechanisms could potentially improve survival in these patients. Research Questions: Which circulating biomarkers and biological mechanisms can distinguish AAA and CAD? Aims: To differentiate the circulating proteomic profiles and biological pathways associated with AAA and CAD. Methods: Patients with AAA and/or stable CAD from two prospective cohort studies were age, sex, and comorbidity matched 1:1:1 (AAA only, AAA and CAD, CAD only). 369 plasma proteins were simultaneously measured in both cohorts using the Olink Explore Cardiometabolic I panel. We investigated differences in proteomic profiles using univariable linear regression and multivariable logistic elastic net regression. Differences in biomarker interactions(pathways) were studied through differential network analysis. Results: Each matched group consisted of 53 patients. Overall, the mean age was 70 years and 92% were men. In AAA-patients, the baseline median(25 th -75 th percentile) maximum diameter was 46(43,50) mm. The proteins IRAG2 and CORO1A were significantly downregulated in AAA-patients with CAD, compared to AAA only. After multivariable selection, only IRAG2 was independently associated with the presence of CAD in AAA-patients. Protein interactions in six pathways differed in AAA-patients with CAD, compared to AAA only(Figure 1A). Moreover, the IGFBP7, CD59, REG1A and CST3 proteins were univariably, significantly upregulated in CAD-patients with AAA, compared to CAD only. Multivariable selection in the proteomic profile proposed PLA2G2A, CD59 and REG1A as independently informative biomarkers for the presence of AAA in CAD-patients. In 14 biological pathways, proteins interacted differently in CAD-patients with AAA, compared to CAD only(Figure 1B). Conclusion(s): A small set of proteins differed between phenotypes. While the average level of most biomarkers was the same, many protein interactions, in pathways implied in AAA by basic research, differed between AAA- and CAD-patients.

No abstract is provided for this article.