CRT-100.04 Delaying Reperfusion Plus LV Unloading Reduces Infarct Size: A Per-Protocol-Analysis of the STEMI_DTU Pilot Study

Background: Myocardial infarct size (IS) and microvascular obstruction (MVO) are well-established prognostic markers in STEMI. The STEMI-DTU pilot trial was the first exploratory study to identify that LV unloading and delayed reperfusion was feasible. We now report new findings in patients from per-protocol cohort on the basis of magnitude of sum of precordial ST-segment elevation. Method: In a multicenter, prospective, randomized safety and feasibility trial, 50 patients with anterior STEMI to LV unloading using Impella CP were assigned into two different arms including immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). Cardiac magnetic resonance (CMR) imaging assessed infarct size normalized to the area at risk (IS/AAR) 3-5 days after PCI. Patients without CMR at 3-5 days, without PCI of a culprit LAD lesion and without STEMI were not per-protocol and thus excluded from this analysis. Results: 32 patients meeting all inclusion and exclusion criteria (U-IR,n=15; U-DR,n=17) were included in our analysis. Despite longer symptom-to-balloon times in the U-DR arm, IS/AAR was significantly lower with 30 minutes of delay to reperfusion in the presence of active LV unloading (47±16% vs 60±15%, p=0.02) and remained lower irrespective of the magnitude of precordial ΣSTE (Figure 1). MVO was not significantly different between groups (1.5±2.8% vs 3.5±4.8%,p=0.15), but significantly lower in the U-DR arm among patients with precordial ΣSTE≥8mm (1.5±2.5% vs 5.6±5.3%, p=0.04). Conclusion: This analysis supports the paradigm-changing concept that when treated per protocol, 30 minutes of delay to reperfusion with active LV unloading may reduce infarct size irrespective of precordial STE magnitude. Ongoing STEMI-DTU Pivotal trial will provide us further information on these findings

TCT-34 Reduction of Infarct Size in Anterior ST-Segment Elevation Myocardial Infarction (STEMI) With LAD Occlusion and LV Unloading Using a Micro-axial Pump for 30 Minutes Before PCI: Per-Protocol Analysis of the STEMI Door to Unload (DTU) Pilot Study

Background: The STEMI-DTU pilot trial identified that LV unloading before PCI is safe and feasible in anterior STEMI without shock. We now report findings from patients who met all protocol inclusion and exclusion criteria. Methods: In a multicenter, randomized safety and feasibility trial, 50 patients with anterior STEMI were unloaded using the Impella CP followed by immediate (U-IR) or delayed PCI after 30 minutes of unloading (U-DR). Cardiac magnetic resonance (CMR) imaging assessed infarct size 3-5 days after PCI. Patients without CMR at 3-5 days (n = 10; 5/arm), without PCI of a culprit LAD lesion (n = 2; 1/arm) and without STEMI (n = 5; 4 U-IR, 1 U-DR) were not per protocol and thus excluded. Results: 33 patients met all inclusion and exclusion criteria (U-IR n = 15, U-DR n = 18) with respective door-to-balloon times of 75 ± 26 and 89 ± 23 minutes (P = 0.10) and mean unload-to-balloon times of 10 ± 5 and 34 ± 3 (P \u3c 0.01). In the total cohort 2-5 day IS was significantly associated with microvascular obstruction (MVO), 30-day IS normalized to total LV mass, 90 day LVEF, and 90 day LV end systolic volume with or without delayed reperfusion (Table) (R \u3e 0.5, P \u3c 0.005 for all). Despite longer symptom to balloon times in the U-DR arm (174 ± 59 vs 228 ± 78, P \u3c 0.01) IS/AAR was lower in the U-DR arm (62 ± 16 vs 48 ± 16, P = 0.04) and remained lower irrespective of STE magnitude. MVO was lower in the U-DR arm among patients with the highest STE (Figure). Conclusion: A per-protocol analysis of the STEMI-DTU Pilot trial identified reduced infarct size with unloading and delayed reperfusion. These findings are under investigation in the STEMI-DTU Pivotal trial. Categories: CORONARY: Acute Myocardial Infarctio

Gravitating discs around black holes

Fluid discs and tori around black holes are discussed within different approaches and with the emphasis on the role of disc gravity. First reviewed are the prospects of investigating the gravitational field of a black hole--disc system by analytical solutions of stationary, axially symmetric Einstein's equations. Then, more detailed considerations are focused to middle and outer parts of extended disc-like configurations where relativistic effects are small and the Newtonian description is adequate. Within general relativity, only a static case has been analysed in detail. Results are often very inspiring, however, simplifying assumptions must be imposed: ad hoc profiles of the disc density are commonly assumed and the effects of frame-dragging and completely lacking. Astrophysical discs (e.g. accretion discs in active galactic nuclei) typically extend far beyond the relativistic domain and are fairly diluted. However, self-gravity is still essential for their structure and evolution, as well as for their radiation emission and the impact on the environment around. For example, a nuclear star cluster in a galactic centre may bear various imprints of mutual star--disc interactions, which can be recognised in observational properties, such as the relation between the central mass and stellar velocity dispersion.Comment: Accepted for publication in CQG; high-resolution figures will be available from http://www.iop.org/EJ/journal/CQ

Advances in structure elucidation of small molecules using mass spectrometry

The structural elucidation of small molecules using mass spectrometry plays an important role in modern life sciences and bioanalytical approaches. This review covers different soft and hard ionization techniques and figures of merit for modern mass spectrometers, such as mass resolving power, mass accuracy, isotopic abundance accuracy, accurate mass multiple-stage MS(n) capability, as well as hybrid mass spectrometric and orthogonal chromatographic approaches. The latter part discusses mass spectral data handling strategies, which includes background and noise subtraction, adduct formation and detection, charge state determination, accurate mass measurements, elemental composition determinations, and complex data-dependent setups with ion maps and ion trees. The importance of mass spectral library search algorithms for tandem mass spectra and multiple-stage MS(n) mass spectra as well as mass spectral tree libraries that combine multiple-stage mass spectra are outlined. The successive chapter discusses mass spectral fragmentation pathways, biotransformation reactions and drug metabolism studies, the mass spectral simulation and generation of in silico mass spectra, expert systems for mass spectral interpretation, and the use of computational chemistry to explain gas-phase phenomena. A single chapter discusses data handling for hyphenated approaches including mass spectral deconvolution for clean mass spectra, cheminformatics approaches and structure retention relationships, and retention index predictions for gas and liquid chromatography. The last section reviews the current state of electronic data sharing of mass spectra and discusses the importance of software development for the advancement of structure elucidation of small molecules

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Transvalvular Ventricular Unloading Before Reperfusion in Acute Myocardial Infarction

BACKGROUND: Myocardial damage due to acute ST-segment elevation myocardial infarction (STEMI) remains a significant global health problem. New approaches to limit myocardial infarct size and reduce progression to heart failure after STEMI are needed. Mechanically reducing left ventricular (LV) workload (LV unloading) before coronary reperfusion is emerging as a potential approach to reduce infarct size. OBJECTIVES: Given the central importance of mitochondria in reperfusion injury, we hypothesized that compared with immediate reperfusion (IR), LV unloading before reperfusion improves myocardial energy substrate use and preserves mitochondrial structure and function. METHODS: To explore the effect of LV unloading duration on infarct size, we analyzed data from the STEMI-Door to Unload (STEMI-DTU) trial and then tested the effect of LV unloading on ischemia and reperfusion injury, cardiac metabolism, and mitochondrial function in swine models of acute myocardial infarction. RESULTS: The duration of LV unloading before reperfusion was inversely associated with infarct size in patients with large anterior STEMI. In preclinical models, LV unloading reduced the expression of hypoxia-sensitive proteins and myocardial damage due to ischemia alone. LV unloading with a transvalvular pump (TV-P) but not with venoarterial extracorporeal membrane oxygenation (ECMO) reduced infarct size. Using unbiased and blinded metabolic profiling, TV-P improved myocardial energy substrate use and preserved mitochondrial structure including cardiolipin content after reperfusion compared with IR or ECMO. Functional testing in mitochondria isolated from the infarct zone showed an intact mitochondrial structure including cardiolipin content, preserved activity of the electron transport chain including mitochondrial complex I, and reduced oxidative stress with TV-P-supported reperfusion but not with IR or ECMO. CONCLUSIONS: These novel findings identify that transvalvular unloading limits ischemic injury before reperfusion, improves myocardial energy substrate use, and preserves mitochondrial structure and function after reperfusion

Unloading the Left Ventricle Before Reperfusion in Patients With Anterior ST-Segment-Elevation Myocardial Infarction

BACKGROUND: In ST-segment-elevation myocardial infarction (STEMI), infarct size correlates directly with heart failure and mortality. Preclinical testing has shown that, in comparison with reperfusion alone, mechanically unloading the left ventricle (LV) before reperfusion reduces infarct size and that 30 minutes of unloading activates a cardioprotective program that limits reperfusion injury. The DTU-STEMI pilot trial (Door-To-Unload in STEMI Pilot Trial) represents the first exploratory study testing whether LV unloading and delayed reperfusion in patients with STEMI without cardiogenic shock is safe and feasible. METHODS: In a multicenter, prospective, randomized exploratory safety and feasibility trial, we assigned 50 patients with anterior STEMI to LV unloading by using the Impella CP followed by immediate reperfusion (U-IR) versus delayed reperfusion after 30 minutes of unloading (U-DR). The primary safety outcome was a composite of major adverse cardiovascular and cerebrovascular events at 30 days. Efficacy parameters included the assessment of infarct size by using cardiac magnetic resonance imaging. RESULTS: All patients completed the U-IR (n=25) or U-DR (n=25) protocols with respective mean door-to-balloon times of 72 versus 97 minutes. Major adverse cardiovascular and cerebrovascular event rates were not statistically different between the U-IR versus U-DR groups (8% versus 12%, respectively, P=0.99). In comparison with the U-IR group, delaying reperfusion in the U-DR group did not affect 30-day mean infarct size measured as a percentage of LV mass (15±12% versus 13±11%, U-IR versus U-DR, P=0.53). CONCLUSIONS: We report that LV unloading using the Impella CP device with a 30-minute delay before reperfusion is feasible within a relatively short time period in anterior STEMI. The DTU-STEMI pilot trial did not identify prohibitive safety signals that would preclude proceeding to a larger pivotal study of LV unloading before reperfusion. An appropriately powered pivotal trial comparing LV unloading before reperfusion to the current standard of care is required. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03000270