Acute, in-Hospital Outcome of Percutaneous Coronary Intervention for In-Stent Chronic Total Occlusion

Background: Percutaneous coronary intervention (PCI) of total chronic total occlusion (CTO) still remains a major challenge in interventional cardiology. Recanalization of in-stent CTO (IS-CTO) is associated with inferior success rates. This present study aims to comparatively evaluate the acute outcome of patients with IS-CTO and de novo CTO. Methods: Between 2012 and 2018 we included 600 patients. Antegrade and retrograde CTO-PCI techniques were used and the primary endpoint was a composite safety endpoint comprising in-hospital death, vascular complications, cardiac tamponade, stroke and acute myocardial infarction. Results: IS-CTO predominantly occurred in the right coronary artery (71.2%). The success (p = 0.495) and complication rates (p = 0.255) were independent of the target vessel. The lesion lengths of IS-CTO were longer than in de-novo CTO (40 mm vs. 30 mm, statistical trend p = 0.081) alongside with the implanted stent lengths (76 mm vs. 63 mm, statistical trend p = 0.070) and their diameter (3.5 mm vs. 3.0 mm, p < 0.001). We determined that procedural and fluoroscopy time were longer in patients with IS-CTO (115.0 min vs. 93.0 min, p = 0.018 and 40.0 min vs. 30.0 min, p = 0.040) and that in this group of patients the amount of contrast medium was higher (250 ml vs. 200 ml, p = 0.015). Overall success rates were comparable between the two group of patients (87.9% vs. 84.4%, p = 0.586). In-hospital, acute procedural complications regarding the composite safety were rare and showed no statistically significant difference (3.0% vs. 5.6%; p = 0.563). Conclusions: Recanalization of in-stent CTO lesions go along with long procedural and high fluoroscopy times as well as an increased amount of contrast medium. Compared to de novo CTO they can be performed safe in experienced hands with similar success rates. (C) 2018 Elsevier Inc. All rights reserved

In-Hospital Outcomes After Recanalization of Ostial Chronic Total Occlusions

Background: Percutaneous coronary intervention (PCI) of chronic total occlusion (CTO) still remains a major challenge in interventional cardiology. Recanalization of ostial lesions is challenging and complex. This present study aims to evaluate the outcome of patients with ostial and non-ostial CTO-PCI with regard to acute, in-hospital outcome. Methods: Between 2012 and 2018 we included 600 patients. Ostial lesions (OL) were defined as a coronary arterial stenosis within 3 mm of the vessel origin. Antegrade and retrograde CTO-PCI techniques were used and a composite safety endpoint comprising in-hospital death, vascular complications, cardiac tamponade, stroke and acute myocardial infarction. Results: The majority of the patients were male (82.3%) and the mean age was 62.1 years (+/- 10.3 years). The right coronary artery (RCA) was the most frequent target vessel in 58.5%, followed by the left circumflex artery (LCX) (15.4%) and the left anterior descending artery (LAD) (26.2%). The success (p = .439) and complication rates (p = .169) were independent of the target vessel. We determined that examination and fluoroscopy time were longer in patients with OL (120.7 min vs. 99.0 min, p < .001 and 44.9 min vs. 34.5 min, p < .001) and that in this group of patients the retrograde approach was used more frequent (38.8% vs. 18.2%, p < .001). Overall success rates were lower in OL than compared to NOL (74.6% vs. 86.5%, p = .016). Conclusions: Our retrospective study suggests that recanalization of ostial CTO lesions is associated with reduced PCI success rates as well as long examination and high fluoroscopy times. (C) 2019 Elsevier Inc. All rights reserved

Impact of body mass index on acute outcome in percutaneous coronary intervention of chronic total occlusion

Background: Percutaneous coronary intervention (PCI) of total chronic total occlusion (CTO) still remains a major challenge in interventional cardiology. There is only insignificant knowledge reported in the literature about the influence of body mass index (BMI) on acute outcome, including success rates and complications in CTO-PCI. Methods: Between 2012 and 2017, we included 508 patients. They underwent PCI for at least one CTO. Antegrade and retrograde CTO techniques were applied. The retrograde approach was used only after failed antegrade intervention. BMI was calculated according to the definitions of the World Health Organization. It was subdivided as normal weight (18.5-24.9 kg/m(2)), overweight (25-29.9 kg/m(2)), obese (30-34.9 kg/m(2)), and very obese (>= 35 kg/m(2)). The Shapiro-Wilk test was used to test for normality of distribution. Continuous variables were tested for differences with Kruskal-Wallis or Mann-Whitney U test as appropriate. Categorical variables were tested with Fisher exact test. Results: Out of the 508 patients, 77 (15.2%) had normal weight, 286 (56.3%) were overweight, 106 (20.9%) obese, and 39 (7.7%) very obese. Radiation dose and examination time increased with elevated BMI categories (p < 0.001, p = 0.026). Success rates were similar in all BMI categories (p = 0.645). In-hospital procedural complications were rare and showed no statistically significant difference (p = 0.185). Conclusions: Our retrospective study suggests that there exists no significant association between overweight and acute outcome in patients undergoing CTO-PCI. It is safe and feasible to perform. (C) 2019 The Authors. Production and hosting by Elsevier B.V

Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling

Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling. Objective: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias. Methods and Results: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin-deficient (CD11b(-/-)) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo(-/-)) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wildtype mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo(-/-) mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H2O2 incubation. Mapping of induced pluripotent stem cell-derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo(-/-) mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter-defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction >35% undergoing elective diagnostic cardiac evaluation. Conclusions: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia

Myeloperoxidase Mediates Postischemic Arrhythmogenic Ventricular Remodeling

Rationale: Ventricular arrhythmias remain the leading cause of death in patients suffering myocardial ischemia. Myeloperoxidase, a heme enzyme released by polymorphonuclear neutrophils, accumulates within ischemic myocardium and has been linked to adverse left ventricular remodeling. Objective: To reveal the role of myeloperoxidase for the development of ventricular arrhythmias. Methods and Results: In different murine models of myocardial ischemia, myeloperoxidase deficiency profoundly decreased vulnerability for ventricular tachycardia on programmed right ventricular and burst stimulation and spontaneously as assessed by ECG telemetry after isoproterenol injection. Experiments using CD11b/CD18 integrin–deficient (CD11b−/−) mice and intravenous myeloperoxidase infusion revealed that neutrophil infiltration is a prerequisite for myocardial myeloperoxidase accumulation. Ventricles from myeloperoxidase-deficient (Mpo−/−) mice showed less pronounced slowing and decreased heterogeneity of electric conduction in the peri-infarct zone than wild-type mice. Expression of the redox-sensitive gap junctional protein Cx43 (Connexin 43) was reduced in the peri-infarct area of wild-type compared with Mpo−/− mice. In isolated wild-type cardiomyocytes, Cx43 protein content decreased on myeloperoxidase/H2O2 incubation. Mapping of induced pluripotent stem cell–derived cardiomyocyte networks and in vivo investigations linked Cx43 breakdown to myeloperoxidase-dependent activation of matrix metalloproteinase 7. Moreover, Mpo−/− mice showed decreased ventricular postischemic fibrosis reflecting reduced accumulation of myofibroblasts. Ex vivo, myeloperoxidase was demonstrated to induce fibroblast-to-myofibroblast transdifferentiation by activation of p38 mitogen-activated protein kinases resulting in upregulated collagen generation. In support of our experimental findings, baseline myeloperoxidase plasma levels were independently associated with a history of ventricular arrhythmias, sudden cardiac death, or implantable cardioverter–defibrillator implantation in a cohort of 2622 stable patients with an ejection fraction \u3e35% undergoing elective diagnostic cardiac evaluation. Conclusions: Myeloperoxidase emerges as a crucial mediator of postischemic myocardial remodeling and may evolve as a novel pharmacological target for secondary disease prevention after myocardial ischemia

Discovery and Early Clinical Evaluation of BMS-605339, a Potent and Orally Efficacious Tripeptidic Acylsulfonamide NS3 Protease Inhibitor for the Treatment of Hepatitis C Virus Infection

The discovery of BMS-605339 (<b>35</b>), a tripeptidic inhibitor of the NS3/4A enzyme, is described. This compound incorporates a cyclopropyl­acylsulfonamide moiety that was designed to improve the potency of carboxylic acid prototypes through the introduction of favorable nonbonding interactions within the S1′ site of the protease. The identification of <b>35</b> was enabled through the optimization and balance of critical properties including potency and pharmacokinetics (PK). This was achieved through modulation of the P2* subsite of the inhibitor which identified the isoquinoline ring system as a key template for improving PK properties with further optimization achieved through functionalization. A methoxy moiety at the C6 position of this isoquinoline ring system proved to be optimal with respect to potency and PK, thus providing the clinical compound <b>35</b> which demonstrated antiviral activity in HCV-infected patients