Door-to-unload: left ventricular unloading before reperfusion in ST-elevation myocardial infarction.

ST-elevation myocardial infarction treatment in the modern era has focused on minimizing time of ischemia by reducing door-to-balloon time to limit infarct size and improve survival. Although there have been significant improvements in minimizing time to coronary reperfusion, the incidence of heart failure following a myocardial infarction has remained high. Preclinical studies have shown that unloading the left ventricle for 30 min prior to coronary reperfusion can reduce infarct size and promote myocardial recovery. The DTU-STEMI randomized prospective trial will test the hypothesis that left ventricular unloading for at least 30 min prior to coronary reperfusion will improve infarct size and heart failure-related events as compared with the current standard of care.

Lay abstract Improvements in the treatment of heart attacks over the years have focused on rapidly opening the blocked vessel to limit the amount of heart muscle damage. Although there have been significant improvements in minimizing the time to treatment using various options from medications to balloons and stents, there continues to be a high incidence of heart failure following a heart attack with larger heart attacks leading to more heart failure. Recent studies in animal models have shown that unloading the work of the heart with a temporary heart pump can decrease the size of the heart attack and improve heart muscle recovery. The door-to-unload research program continues to investigate the treatment strategy of unloading the heart for at least 30 min prior to opening the blocked vessel to improve patient outcomes.

Discovery of 6-Oxo-4-phenyl-hexanoic acid derivatives as RORγt inverse agonists showing favorable ADME profile.

The retinoic acid receptor-related orphan nuclear receptor gamma t (RORγt), which is a promising therapeutic target for immune diseases, is a major transcription factor of genes related to psoriasis pathogenesis, such as interleukin (IL)-17A, IL-22, and IL-23R. Inspired by the co-crystal structure of RORγt, a 6-oxo-4-phenyl-hexanoic acid derivative 6a was designed, synthesized, and identified as a ligand of RORγt. The structure-activity relationship (SAR) studies in 6a, which focus on the improvement of its membrane permeability profile by introducing chlorine atoms, led to finding 12a, which has a potent RORγt inhibitory activity and a favorable pharmacokinetic profile.

Discovery of [1,2,4]Triazolo[1,5-a]pyridine Derivatives as Potent and Orally Bioavailable RORγt Inverse Agonists.

The retinoic acid receptor-related orphan nuclear receptor γt (RORγt), a promising therapeutic target, is a major transcription factor of genes related to psoriasis pathogenesis such as interleukin (IL)-17A, IL-22, and IL-23R. On the basis of the X-ray cocrystal structure of RORγt with 1a, an analogue of the known piperazine RORγt inverse agonist 1, triazolopyridine derivatives of 1 were designed and synthesized, and analogue 3a was found to be a potent RORγt inverse agonist. Structure-activity relationship studies on 3a, focusing on the treatment of its metabolically unstable cyclopentyl ring and the central piperazine core, led to a novel analogue, namely, 6-methyl-N-(7-methyl-8-(((2S,4S)-2-methyl-1-(4,4,4-trifluoro-3-(trifluoromethyl)butanoyl)piperidin-4-yl)oxy)[1,2,4]triazolo[1,5-a]pyridin-6-yl)nicotinamide (5a), which exhibited strong RORγt inhibitory activity and a favorable pharmacokinetic profile. Moreover, the in vitro and in vivo evaluation of 5a in a human whole-blood assay and a mouse IL-18/23-induced cytokine expression model revealed its robust and dose-dependent inhibitory effect on IL-17A production.

Potential of the fluoroketolide RBx 14255 against Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae in an experimental murine meningitis model.

BACKGROUND: RBx 14255 is a fluoroketolide in pre-clinical evaluation with potent activity against MDR Gram-positive pathogens. OBJECTIVES: To investigate the efficacy of RBx 14255 against bacterial meningitis caused by Streptococcus pneumoniae, Neisseria meningitidis or Haemophilus influenzae in an experimental murine meningitis model. METHODS: In vitro activity of RBx 14255 was evaluated against clinical isolates of S. pneumoniae, N. meningitidis and H. influenzae. The in vivo efficacy of RBx 14255 was evaluated against bacterial meningitis, induced with S. pneumoniae 3579 erm(B), S. pneumoniae MA 80 erm(B), N. meningitidis 1852 and H. influenzae B1414 in a murine meningitis model. RESULTS: RBx 14255 showed strong in vitro bactericidal potential against S. pneumoniae, N. meningitidis and H. influenzae with MIC ranges of 0.004-0.1, 0.03-0.5 and 1-4 mg/L, respectively. In a murine meningitis model, a 50 mg/kg dose of RBx 14255, q12h, resulted in significant reduction of bacterial counts in the brain compared with the pretreatment control. The concentration of RBx 14255 in brain tissue correlated well with the efficacy in this mouse model. CONCLUSIONS: RBx 14255 showed superior bactericidal activity in time-kill assays in vitro and in vivo in an experimental murine meningitis model. RBx 14255 could be a promising candidate for future drug development against bacterial meningitis.

Fatal or Irreversible Bleeding and Ischemic Events With Rivaroxaban in Acute Coronary Syndrome.

BACKGROUND: Net clinical outcome analyses of acute coronary syndrome (ACS) mingle fatal or irreversible events with survivable or reversible events that vary significantly in clinical impact. OBJECTIVES: A comparison of efficacy and safety limited to fatal or irreversible ischemic and adverse or seriously harmful events is one way to assess net clinical outcome and risk-benefit overall, given the fact that these events have a similar clinical impact. METHODS: In the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction) trial of rivaroxaban in the secondary prevention of events among patients with ACS treated with aspirin plus clopidogrel or ticlopidine (clopidogrel/ticlopidine) or aspirin alone, fatal and irreversible efficacy events including nonbleeding cardiovascular death, myocardial infarction, and ischemic stroke were compared to fatal or irreversible safety events, including fatal and intracranial bleeding. RESULTS: Rivaroxaban, 2.5 mg orally twice per day, in patients treated with aspirin and clopidogrel/ticlopidine was associated with 115 (95% confidence interval [CI]: 18 to 212) fewer fatal or irreversible ischemic events (663 for placebo vs. 548 for therapy) and 10 (95% CI: -11 to 32) additional fatal or irreversible seriously harmful events (33 vs. 23 for placebo) per 10,000 patient-years of exposure. Taken together, there would be 105 (95% CI: 6 to 204) fatal or irreversible events prevented per 10,000 patient-years of exposure to rivaroxaban compared with placebo, with 11 (10 of 115) fatal or irreversible ischemic events prevented for each fatal or irreversible seriously harmful event caused. If only nonbleeding cardiovascular death is included as a fatal or irreversible event, then 95 events would be prevented per 10,000 patient-years of exposure in the group taking 2.5 mg orally twice per day. CONCLUSIONS: Both fatal or irreversible ischemia and bleeding are clinically significant events that can be compared to assess the net clinical outcomes associated with therapy. Rivaroxaban therapy at an oral dose of 2.5 mg twice daily in patients treated with aspirin and clopidogrel is associated with a net reduction in fatal or irreversible events. (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction [ATLAS ACS 2-TIMI 51]; NCT00809965).

EMBRACE STEMI study: a Phase 2a trial to evaluate the safety, tolerability, and efficacy of intravenous MTP-131 on reperfusion injury in patients undergoing primary percutaneous coronary intervention.

AIMS: Among patients with ST-elevation myocardial infarction (STEMI), reperfusion injury contributes to additional myocardial damage. MTP-131 is a cell-permeable peptide that preserves the integrity of cardiolipin, enhances mitochondrial energetics, and improves myocyte survival during reperfusion. METHODS AND RESULTS: EMBRACE STEMI is a multicentre, randomized, double-blind Phase 2a trial that evaluated the efficacy and safety of MTP-131 vs. placebo infused at a rate of 0.05 mg/kg/h for 1 h among first-time anterior STEMI subjects undergoing primary percutaneous coronary intervention (PCI) for a proximal or mid left anterior descending (LAD) artery occlusion. Administration of MTP-131 was not associated with a significant reduction in the primary endpoint, infarct size by creatine kinase-myocardial band (CK-MB) area under the curve (AUC) over 72 h (5785 ± 426 ng h/mL in placebo vs. 5570 ± 486 ng h/mL in MTP-131; ITALIC! P = NS). MTP-131 was not associated with an improvement in pre-specified magnetic resonance imaging, angiographic, electrocardiographic, or clinical outcomes. CONCLUSION: Among subjects with first-time anterior STEMI due to a proximal or mid LAD lesion who undergo successful PCI, administration of MTP-131 was safe and well tolerated. Treatment with MTP-131 was not associated with a decrease in myocardial infarct size as assessed by AUC0-72 of CK-MB.

Utility of a real-time appropriate use criteria decision support application for percutaneous coronary interventions in non-acute coronary syndrome.

OBJECTIVES: The aim of this study was to test the feasibility and value of a real-time online appropriate use criteria (AUC) application for percutaneous coronary intervention (PCI) in patients without acute coronary syndrome. BACKGROUND: High rates of non-appropriate elective PCI in the National Cardiovascular Data Registry (NCDR) CathPCI Registry have created interest in integrating decision support tools into routine clinical care to improve the frequency of appropriate PCIs. METHODS: Patients undergoing diagnostic coronary angiography and subsequent PCI for non-ACS indications at a single center were scored using a real-time AUC application pre-procedure. Blinded angiographic review was performed subsequently for each case. Rates of appropriate, inappropriate, uncertain and not rated PCIs were tabulated according to specific clinical scenarios using information available both before and after the angiographic audit. RESULTS: Of 308 PCIs in 272 patients, 196 (63.6%) were deemed appropriate, 79 (25.6%) uncertain, and two (0.6%) inappropriate; 31 (10.1%) scenarios could not be rated. With angiographic audit, inappropriate PCIs increased to 9.7%. There was a significant improvement in the rate of appropriate PCI using the real-time AUC application compared with retrospective data collection for NCDR reporting (64% vs. 53%, P = 0.01). CONCLUSIONS: Use of a real-time AUC application together with angiographic audit may improve the accuracy of reporting PCI appropriateness. © 2015 Wiley Periodicals, Inc.

A novel ketolide, RBx 14255, with activity against multidrug-resistant Streptococcus pneumoniae.

We present here the novel ketolide RBx 14255, a semisynthetic macrolide derivative obtained by the derivatization of clarithromycin, for its in vitro and in vivo activities against sensitive and macrolide-resistant Streptococcus pneumoniae. RBx 14255 showed excellent in vitro activity against macrolide-resistant S. pneumoniae, including an in-house-generated telithromycin-resistant strain (S. pneumoniae 3390 NDDR). RBx 14255 also showed potent protein synthesis inhibition against telithromycin-resistant S. pneumoniae 3390 NDDR. The binding affinity of RBx 14255 toward ribosomes was found to be more than that for other tested drugs. The in vivo efficacy of RBx 14255 was determined in murine pulmonary infection induced by intranasal inoculation of S. pneumoniae ATCC 6303 and systemic infection with S. pneumoniae 3390 NDDR strains. The 50% effective dose (ED50) of RBx 14255 against S. pneumoniae ATCC 6303 in a murine pulmonary infection model was 3.12 mg/kg of body weight. In addition, RBx 14255 resulted in 100% survival of mice with systemic infection caused by macrolide-resistant S. pneumoniae 3390 NDDR at 100 mg/kg four times daily (QID) and at 50 mg/kg QID. RBx 14255 showed favorable pharmacokinetic properties that were comparable to those of telithromycin.

Angiographic validation of the American College of Cardiology Foundation-the Society of Thoracic Surgeons Collaboration on the Comparative Effectiveness of Revascularization Strategies study.

BACKGROUND: The goal of this study was to compare angiographic interpretation of coronary arteriograms by sites in community practice versus those made by a centralized angiographic core laboratory. METHODS AND RESULTS: The study population consisted of 2013 American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR) records with 2- and 3- vessel coronary disease from 54 sites in 2004 to 2007. The primary analysis compared Registry (NCDR)-defined 2- and 3-vessel disease versus those from an angiographic core laboratory analysis. Vessel-level kappa coefficients suggested moderate agreement between NCDR and core laboratory analysis, ranging from kappa=0.39 (95% confidence intervals, 0.32-0.45) for the left anterior descending artery to kappa=0.59 (95% confidence intervals, 0.55-0.64) for the right coronary artery. Overall, 6.3% (n=127 out of 2013) of those patients identified with multivessel disease at NCDR sites had had 0- or 1-vessel disease by core laboratory reading. There was no directional bias with regard to overcall, that is, 12.3% of cases read as 3-vessel disease by the sites were read as <3-vessel disease by the core laboratory, and 13.9% of core laboratory 3-vessel cases were read as <3-vessel by the sites. For a subset of patients with left main coronary disease, registry overcall was not linked to increased rates of mortality or myocardial infarction. CONCLUSIONS: There was only modest agreement between angiographic readings in clinical practice and those from an independent core laboratory. Further study will be needed because the implications for patient management are uncertain.

Optimizing reperfusion in patients with STEMI: a critical evaluation of pharmacologic and non-pharmacologic strategies.

Among patients with ST-elevation myocardial infarction (STEMI), rapidly re-establishing normal coronary blood flow is of paramount importance. More than 25 % of hospitals in the USA do not have access to timely primary percutaneous coronary intervention, highlighting the need for clinicians to understand both pharmacologic and non-pharmacologic strategies for STEMI. This manuscript reviews the current state of the art in STEMI care, describing both pharmacologic and non-pharmacologic strategies for reperfusion.

Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51.

OBJECTIVES: The aim of this study was to determine if rivaroxaban is associated with a reduction in stent thrombosis among patients with acute coronary syndromes (ACS) in the ATLAS-ACS 2 TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome-Thrombolysis in Myocardial Infarction 51) trial. BACKGROUND: Dual antiplatelet therapy (DAPT) has been the mainstay of efforts to prevent stent thrombosis. Because thrombin is a potent stimulant of platelet activation, we hypothesized that inhibition of thrombin generation via factor Xa inhibition may further reduce the risk of stent thrombosis. METHODS: The ATLAS-ACS 2 TIMI 51 study was a placebo-controlled trial that randomly assigned 15,526 patients with recent ACS to receive twice-daily doses of either 2.5 mg or 5 mg of rivaroxaban or placebo for a mean of 13 months and up to 31 months. RESULTS: Among patients who had a stent placed before or at the time of the index event, rivaroxaban significantly reduced independently adjudicated Academic Research Consortium definite and probable stent thrombosis in the pooled (1.9% vs. 1.5%; hazard ratio [HR]: 0.65; p = 0.017) and the 2.5 mg twice-daily (1.9% vs. 1.5%; HR: 0.61; p = 0.023) treatment groups when compared with placebo, with a trend toward a reduction in the 5 mg twice-daily treatment group (1.9% vs. 1.5%; HR: 0.70; p = 0.089). Among patients who received both aspirin and a thienopyridine (stratum 2), the benefit of rivaroxaban emerged during the period of active treatment with DAPT (HR: 0.68; 95% CI: 0.50 to 0.92, combined rivaroxaban group vs. placebo). Among stented patients who were treated with dual antiplatelet therapy, there was a mortality reduction among those treated with twice-daily rivaroxaban 2.5 mg (HR: 0.56; 95% CI: 0.35 to 0.89; p = 0.014). CONCLUSIONS: Among stented patients with ACS treated with DAPT, the administration of twice-daily rivaroxaban 2.5 mg was associated with a reduction in stent thrombosis and mortality. (An Efficacy and Safety Study for Rivaroxaban in Patients With Acute Coronary Syndrome; NCT00809965).

Rationale and design of the EMBRACE STEMI study: a phase 2a, randomized, double-blind, placebo-controlled trial to evaluate the safety, tolerability and efficacy of intravenous Bendavia on reperfusion injury in patients treated with standard therapy including primary percutaneous coronary intervention and stenting for ST-segment elevation myocardial infarction.

BACKGROUND: Although significant efforts have been made to improve ST-segment elevation myocardial infarction (STEMI) outcomes by reducing symptom-onset-to-reperfusion times, strategies to decrease the clinical impact of ischemic reperfusion injury have demonstrated limited success. Bendavia, an intravenously administered mitochondrial targeting peptide, has been shown to reduce myocardial infarct size and attenuate coronary no-reflow in experimental modelswhen given before reperfusion. DESIGN: The EMBRACE STEMI study is a phase 2a, randomized, double-blind, placebo-controlled trial enrolling 300 patients with a first-time anterior STEMI and an occluded proximal or mid-left anterior descending artery undergoing primary percutaneous coronary intervention (PCI) within 4 hours of symptom onset. Patients will be randomized to receive either Bendavia at 0.05 mg/kg per hour or an identically appearing placebo administered as an intravenous infusion at 60 mL/h. The primary end point is infarct size measured by the area under the creatine kinase-MB enzyme curve calculated from measurements from the central clinical chemistry laboratory obtained over the initial 72 hours after the primary PCI procedure, and the major secondary end point is infarct size calculated by the volume of infarcted myocardium (late contrast gadolinium enhancement) on the day 4±1 cardiac magnetic resonance imaging. SUMMARY: EMBRACE-STEMI is testing the hypothesis that Bendavia, in conjunction with standard-of-care therapy, is superior to placebo for the reduction of myocardial infarction size among patients with first time, acute, anterior wall STEMI who undergo successful reperfusion with primary PCI and stenting.

Mechanical circulatory support for right ventricular failure.

OBJECTIVES: The aim of this study was to explore the clinical utility of a commercially available centrifugal flow pump as a centrifugal flow-right ventricular support device (CF-RVSD) in patients with right ventricular failure (RVF). BACKGROUND: RVF is associated with high in-hospital mortality. Limited data regarding efficacy of the CF-RVSD for RVF exist. METHODS: We retrospectively reviewed data from 46 patients receiving a CF-RVSD for RVF from a registry comprising data from 8 tertiary-care hospitals in the United States. CF-RVSD use was recorded in the setting of acute myocardial infarction; myocarditis; chronic left heart failure; after valve surgery, orthotopic heart transplantation, left ventricular assist device surgery, coronary bypass grafting. Devices were implanted via the percutaneous (n = 22) or surgical (n = 24) route. RESULTS: No intraprocedural mortality was observed. Mean time from admission to CF-RVSD implantation was 5.7 ± 8.5 days, with a mean of 6,769 ± 789 rotations/min, providing 4.2 ± 1.3 l/min of flow. Mean duration of support was 5.4 ± 5.1 days. Mean arterial pressure (65 ± 12 mm Hg vs. 73 ± 14 mm Hg; p < 0.05), right atrial pressure (21 ± 8 mm Hg vs. 16 ± 7 mm Hg; p = 0.05), pulmonary artery systolic pressure (43 ± 15 mm Hg vs. 33 ± 15 mm Hg; p = 0.01), and cardiac index (1.7 ± 0.7 vs. 2.2 ± 0.6; p = 0.01) were improved within 48 h of CF-RVSD implantation. Total in-hospital mortality was 57% and was lowest in the setting of left ventricular assist device implantation, chronic left heart failure, and acute myocardial infarction. Increased age, biventricular failure, and Thrombolysis In Myocardial Infarction-defined major bleeding were associated with increased in-hospital mortality. CONCLUSIONS: Use of the CF-RVSD for RVF is clinically feasible and associated with improved hemodynamic status. Observations from the registry of patients who have received this device may support the development of prospective studies that will examine the role of percutaneous circulatory support for RVF.

Optimal selection of STEMI treatment strategies in the current era: benefit of transferring STEMI patients for PCI compared with administration of onsite fibrinolytic therapy.

PURPOSE OF REVIEW: For patients presenting with ST-elevation myocardial infarction (STEMI), primary percutaneous coronary intervention (PPCI) is superior to onsite fibrinolytic therapy (O-FT) when administered in a timely fashion. This benefit diminishes as PCI-related delay increases. This review examines recent data exploring this relationship, offering insight into possible mechanisms for the time-dependent benefit of PCI. RECENT FINDINGS: The advantage of transfer for primary PCI (X-PCI) over O-FT was analyzed in a contemporary propensity-score matched cohort by evaluating outcomes based on PCI-related delay (door-to-balloon time minus door-to-needle time). In 19 012 matched STEMI patients from the National Registry of Myocardial Infarction database, the delay to PCI wherein the mortality advantage for X-PCI was nullified compared with O-FT was approximately 120 min. Extensive delays were found to attenuate the mortality benefit of X-PCI [number needed to treat (NNT) 23 for PCI-related delay >60 min; NNT 44 for PCI-related delay 60-90 min; and NNT 250 for PCI-related delay >90 min]. SUMMARY: The benefit of PCI over O-FT appears to markedly decrease as PCI-related delay increases, particularly in the case of interhospital transfer, which can often lead to long reperfusion times. Various strategies can reduce PCI-related delays, including the establishment of STEMI systems of care and regionalization. Furthermore, alternate pharmacoinvasive strategies should be considered when significant delay to PCI is anticipated.

In vitro and in vivo activities of the novel Ketolide RBx 14255 against Clostridium difficile.

The MIC(90) of RBx 14255, a novel ketolide, against Clostridium difficile was 4 µg/ml (MIC range, 0.125 to 8 µg/ml), and this drug was found to be more potent than comparator drugs. An in vitro time-kill kinetics study of RBx 14255 showed time-dependent bacterial killing for C. difficile. Furthermore, in the hamster model of C. difficile infection, RBx 14255 demonstrated greater efficacy than metronidazole and vancomycin, making it a promising candidate for C. difficile treatment.

Admission hyperglycemia and acute myocardial infarction: outcomes and potential therapies for diabetics and nondiabetics.

Hyperglycemia, in both diabetic and nondiabetic patients, has a significant negative impact on the morbidity and mortality of patients presenting with an acute myocardial infarction (AMI). Contemporary evidence indicates that persistent hyperglycemia after initial hospital admission continues to exert negative effects on AMI patients. There have been a number of studies demonstrating the benefit of tight glucose control in patients presenting with AMI, but a lack of convincing clinical data has led to loose guidelines and poor implementation of glucose targets for this group of patients. The CREATE-ECLA study, which hypothesized that a fixed high dose of glucose, insulin, and potassium (GIK) would change myocardial substrate utilization from free fatty acids to glucose and therefore protect ischemic myocardium, failed to demonstrate improved clinical outcomes in AMI patients. Studies that specifically investigated intensive insulin therapy, including DIGAMI-2 and HI-5, also failed to improve clinical outcomes such as mortality. There are a number of reasons that these trials may have fallen short, including the inability to reach glucose targets and inadequate power. There is now a need for a large placebo-controlled randomized trial with an adequate sample size and adherence to glucose targets in order to establish the benefit of treating hyperglycemia in patients presenting with AMI.

Interrogating inclusive development in India's transition process.

This paper makes two related contributions. First, the dual economic structure underlying development is shown as producing a distinct conception of other comprising of a devalued third world which is foregrounded and world of the third which is excluded. This dyad of inclusion-exclusion of other is produced in relation to the centers of capitalism and modernism. The category of third world helps to displace the language-experience-logic-ethos of the other a la world of the third such that development works over and transforms world of the third, but via the trope of a devalued third world. We then use this framework to explore the relation of global capitalism with world of the third in the Indian context, a relation that is shown to be two fold. There is on one hand an attempt to dismantle world of the third as part of the development trope of overcoming the third world. On the other, through inclusive development, an attempt is made to directly intervene in the economy of world of the third so as to address the problems of income inequality and social exclusion, again under the trope of uplifting the devalued third world.

Newer Pharmaceutical Agents for STEMI Interventions.

ST-elevation myocardial infarction (STEMI) causes 12.6% of deaths worldwide. Treatment strategies involve early revascularization by percutaneous coronary intervention and/or fibrinolytics, with adjunctive pharmacologic therapy. While antiplatelet therapy remains the cornerstone of pharmacologic management, newer antithrombotic therapies are showing benefit in the reduction of long-term thrombotic events following acute vessel occlusion. Future directions in adjunctive STEMI management include the use of hematopoietic stem cell therapy or growth factors to induce proliferation and differentiation of cardiac myocytes.