Decreased coronary flow reserve in hypertrophic cardiomyopathy is related to remodeling of the coronary microcirculation

BACKGROUND: Ischemia occurs frequently in hypertrophic cardiomyopathy (HCM) without evidence of epicardial stenosis. This study evaluates the hypothesis that the occurrence of ischemia in HCM is related to remodeling of the coronary microcirculation. METHODS AND RESULTS: End-diastolic septal wall thickness was significantly increased in patients with HCM (25.8+/-2.9 mm) in comparison with cardiac transplant recipients (control subjects: 11.4+/-3.0 mm; P<0.05). Although the diameter of the left anterior descending coronary artery was similar in both groups (3.0+/-0.8 versus 3.0+/-0.5 mm, P=NS), the coronary resistance reserve (CRR=CRRbasal/CRRhyperemic), corrected for extravascular compression (end-diastolic left ventricular pressure), was reduced to 1.5+/-0.6 in HCM (P<.05; control, 2.6+/-0.8). Arteriolar lumen (AL) divided by wall area was lower in HCM (21+/-5% versus 30+/-4%; P<.05), and capillary density tended to decrease (from 1824+/-424 to 1445+/-513 per mm2, P=.11) in HCM. CRR was linearly related to normalized AL according to the formula CRR=O.1 AL-0.45 (r=.57; P<.05). Further analysis revealed that CRR, AL, and capillary density were all linearly related to the degree of hypertrophy. CONCLUSIONS: Decrements in CRR were related to changes of the coronary microcirculation. Both the decrease in CRR and these changes in the coronary microcirculation were related to the degree of hypertrophy. All these factors might contribute to the well-known occurrence of ischemia in this patient group

Limitation of Infarct Size and No-Reflow by Intracoronary Adenosine Depends Critically on Dose and Duration

AbstractObjectivesIn the absence of effective clinical pharmacotherapy for prevention of reperfusion-mediated injury, this study re-evaluated the effects of intracoronary adenosine on infarct size and no-reflow in a porcine model of acute myocardial infarction using clinical bolus and experimental high-dose infusion regimens.BackgroundDespite the clear cardioprotective effects of adenosine, when administered prior to ischemia, studies on cardioprotection by adenosine when administered at reperfusion have yielded contradictory results in both pre-clinical and clinical settings.MethodsSwine (54 ± 1 kg) were subjected to a 45-min mid–left anterior descending artery occlusion followed by 2 h of reperfusion. In protocol A, an intracoronary bolus of 3 mg adenosine injected over 1 min (n = 5) or saline (n = 10) was administered at reperfusion. In protocol B, an intracoronary infusion of 50 μg/kg/min adenosine (n = 15) or saline (n = 21) was administered starting 5 min prior to reperfusion and continued throughout the 2-h reperfusion period.ResultsIn protocol A, area-at-risk, infarct size, and no-reflow were similar between groups. In protocol B, risk zones were similar, but administration of adenosine resulted in significant reductions in infarct size from 59 ± 3% of the area-at-risk in control swine to 46 ± 4% (p = 0.02), and no-reflow from 49 ± 6% of the infarct area to 26 ± 6% (p = 0.03).ConclusionsDuring reperfusion, intracoronary adenosine can limit infarct size and no-reflow in a porcine model of acute myocardial infarction. However, protection was only observed when adenosine was administered via prolonged high-dose infusion, and not via short-acting bolus injection. These findings warrant reconsideration of adenosine as an adjuvant therapy during early reperfusion

An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE

Abstract Background Myelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNγ receptor (IFNγR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNγ-dependent pathways that regulate their production remain to be elucidated. Methods The spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry. Results CNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNγRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNγ directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNγ. Conclusions We provide evidence for an IFNγ-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNγ signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNγ, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNγ and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations.https://deepblue.lib.umich.edu/bitstream/2027.42/145159/1/12974_2018_Article_1237.pd

Space-borne Bose-Einstein condensation for precision interferometry

Space offers virtually unlimited free-fall in gravity. Bose-Einstein condensation (BEC) enables ineffable low kinetic energies corresponding to pico- or even femtokelvins. The combination of both features makes atom interferometers with unprecedented sensitivity for inertial forces possible and opens a new era for quantum gas experiments. On January 23, 2017, we created Bose-Einstein condensates in space on the sounding rocket mission MAIUS-1 and conducted 110 experiments central to matter-wave interferometry. In particular, we have explored laser cooling and trapping in the presence of large accelerations as experienced during launch, and have studied the evolution, manipulation and interferometry employing Bragg scattering of BECs during the six-minute space flight. In this letter, we focus on the phase transition and the collective dynamics of BECs, whose impact is magnified by the extended free-fall time. Our experiments demonstrate a high reproducibility of the manipulation of BECs on the atom chip reflecting the exquisite control features and the robustness of our experiment. These properties are crucial to novel protocols for creating quantum matter with designed collective excitations at the lowest kinetic energy scales close to femtokelvins.Comment: 6 pages, 4 figure

Myeloid cell plasticity in the evolution of central nervous system autoimmunity

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/141100/1/ana25128_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/141100/2/ana25128.pd

An IFNγ/CXCL2 regulatory pathway determines lesion localization during EAE

BackgroundMyelin oligodendrocyte glycoprotein (MOG)-reactive T-helper (Th)1 cells induce conventional experimental autoimmune encephalomyelitis (cEAE), characterized by ascending paralysis and monocyte-predominant spinal cord infiltrates, in C57BL/6 wildtype (WT) hosts. The same T cells induce an atypical form of EAE (aEAE), characterized by ataxia and neutrophil-predominant brainstem infiltrates, in syngeneic IFNγ receptor (IFNγR)-deficient hosts. Production of ELR+ CXC chemokines within the CNS is required for the development of aEAE, but not cEAE. The cellular source(s) and localization of ELR+ CXC chemokines in the CNS and the IFNγ-dependent pathways that regulate their production remain to be elucidated.MethodsThe spatial distribution of inflammatory lesions and CNS expression of the ELR+ CXC chemokines, CXCL1 and CXCL2, were determined via immunohistochemistry and/or in situ hybridization. Levels of CXCL1 and CXCL2, and their cognate receptor CXCR2, were measured in/on leukocyte subsets by flow cytometric and quantitative PCR (qPCR) analysis. Bone marrow neutrophils and macrophages were cultured with inflammatory stimuli in vitro prior to measurement of CXCL2 and CXCR2 by qPCR or flow cytometry.ResultsCNS-infiltrating neutrophils and monocytes, and resident microglia, are a prominent source of CXCL2 in the brainstem of IFNγRKO adoptive transfer recipients during aEAE. In WT transfer recipients, IFNγ directly suppresses CXCL2 transcription in microglia and myeloid cells, and CXCR2 transcription in CNS-infiltrating neutrophils. Consequently, infiltration of the brainstem parenchyma from the adjacent meninges is blocked during cEAE. CXCL2 directly stimulates its own expression in cultured neutrophils, which is enhanced by IL-1 and suppressed by IFNγ.ConclusionsWe provide evidence for an IFNγ-regulated CXCR2/CXCL2 autocrine/paracrine feedback loop in innate immune cells that determines the location of CNS infiltrates during Th1-mediated EAE. When IFNγ signaling is impaired, myeloid cell production of CXCL2 increases, which promotes brainstem inflammation and results in clinical ataxia. IFNγ, produced within the CNS of WT recipients, suppresses myeloid cell CXCR2 and CXCL2 production, thereby skewing the location of neuroinflammatory infiltrates to the spinal cord and the clinical phenotype to an ascending paralysis. These data reveal a novel mechanism by which IFNγ and CXCL2 interact to direct regional recruitment of leukocytes in the CNS, resulting in distinct clinical presentations