Inferior ST segment changes during acute anterior myocardial infarction: A marker of the presence or absence of concomitant inferior wall ischemia

The significance of inferior ST segment changes during acute anterior myocardial infarction was studied in 60 patients with acute anterior infarction who had angiographic visualization of the entire distribution of the left anterior descending artery after thrombolytic therapy with streptokinase. In 34 patients (Group 1) this artery supplied the anterior wall of the left ventricle up to or including the apex but did not reach the inferior wall; in 16 patients (Group 2) it continued beyond the apex onto the inferior wall of the left ventricle; and in 10 patients with prior inferior infarction (Group 3) it partially supplied the inferior wall of the left ventricle through collateral channels to an occluded right or dominant circumflex coronary artery.Consistent with this anatomy, evidence of inferior wall ischemia was significantly more frequent in Groups 2 and 3 than in Group 1 by thallium-201 scintigraphy (91 versus 7%) and by contrast left ventriculography (91 versus 13%). There was no difference in the magnitude of precordial ST segment elevation among the three groups but the inferior ST segment depression was significantly smaller in Groups 2 and 3 with concomitant inferior wall ischemia than in Group 1 (aVF: −0.5 ± 0.7; −0.5 ± 1.0; −1.8 ± 0.8 mm, respectively; p < 0.001) with 10 of the 26 patients in Groups 2 and 3 having an elevated or isoelectric ST segment in aVF compared with none of the 34 patients in Group 1 (p < 0.001). In patients with inferior ST segment depression, a ratio of ST depression in lead aVF to ST elevation in lead V2 that was less negative than −0.2 was a reliable marker of concomitant inferior wall ischemia.The data suggest that the electrocardiogram can identify patients with anterior infarction who have concomitant inferior wall ischemia due to occlusion of a left anterior descending artery that either also supplies the inferior wall or is the source of collateral flow to a previously occluded posterior descending artery in patients with prior inferior infarction

Pacing stress echocardiography: an alternative to pharmacologic stress testing

AbstractOBJECTIVESWe sought to evaluate the diagnostic accuracy and feasibility of bedside pacing stress echocardiography (PASE) as a potential substitute for pharmacologic stress echocardiography in patients admitted to the hospital with new-onset chest pain or worsening angina pectoris.BACKGROUNDAccurate and rapid noninvasive identification and evaluation of the extent of coronary artery disease (CAD) is essential for optimal management of these patients.METHODSBedside transthoracic stress echocardiography was performed in 54 consecutive patients admitted to a community hospital with new-onset chest pain, after acute myocardial infarction had been excluded. We used 10F transesophageal pacing catheters and a rapid and modified pacing protocol. The PASE results were validated in all patients by coronary angiography performed within 24 h of the test. Significant CAD was defined as ≥75% stenosis in at least one major epicardial coronary artery.RESULTSThe sensitivity of PASE for identifying patients with significant CAD was 95%, specificity was 87% and accuracy was 92%. The extent of significant CAD (single- or multivessel disease) was highly concordant with coronary angiography (kappa = 0.73, p < 0.001). Pacing stress echocardiography was well tolerated, and only 4% of the patients had minor adverse events. The mean rate–pressure product at peak pacing was 22,313 ± 5,357 beats/min per mm Hg, and heart rate >85% of the age-predicted target was achieved in 94% of patients. The average duration of the bedside PASE test, including image interpretation, was 38 ± 6 min.CONCLUSIONSBedside PASE is rapid, tolerable and accurate for identification of significant CAD in patients admitted to the hospital with new-onset chest pain or worsening angina pectoris

Immune-modulation by polyclonal IgM treatment reduces atherosclerosis in hypercholesterolemic apoE−/− mice

AbstractObjectiveGamma-globulin treatment reduces experimental atherosclerosis by modulating immune function; however the effect of IgM on atherosclerosis is not known. We investigated the effect of serum-derived, non-immune polyclonal IgM (Poly-IgM) on atherosclerosis in mice with advanced disease and also assessed its immune-modulatory effects.Methods and resultsAortic atherosclerosis was assessed in apoE−/− mice fed atherogenic diet starting at 6 weeks of age. In addition, mice were also subjected to perivascular cuff injury to the carotid artery at 25 weeks of age to induce accelerated atherosclerosis. At the time of injury, the mice were treated weekly with a commercially available Poly-IgM (0.4mg/mouse) or PBS for 4 weeks and euthanized at 29 weeks of age. Poly-IgM reduced aortic atherosclerosis, and reduced lesion size in the aortic sinus and injured carotid artery, without significant changes in serum cholesterol levels. Poly-IgM treatment was associated with increased anti-oxLDL IgG titers and a reduction in the % splenic CD4+ T cells compared to controls. The splenic CD4+ T cell cultured from the Poly-IgM treated mice had reduced proliferation in vitro compared with controls.ConclusionPoly-IgM treatment reduced aortic and accelerated carotid atherosclerosis in apoE−/− mice in association with increased anti-oxLDL IgG titers, and reduced number and proliferative function of splenic CD4+ T cells. Our study identifies a novel athero-protective and immunomodulatory role for non-immune polyclonal IgM

Impaired tolerance to the autoantigen LL-37 in acute coronary syndrome

BackgroundLL-37 is the only member of the cathelicidin family of antimicrobial peptides in humans and is an autoantigen in several autoimmune diseases and in acute coronary syndrome (ACS). In this report, we profiled the specific T cell response to the autoimmune self-antigen LL-37 and investigated the factors modulating the response in peripheral blood mononuclear cells (PBMCs) of healthy subjects and ACS patients.Methods and resultsThe activation induced marker (AIM) assay demonstrated differential T cell profiles characterized by the persistence of CD134 and CD137, markers that impair tolerance and promote immune effector and memory response, in ACS compared to Controls. Specifically, CD8+CD69+CD137+ T cells were significantly increased by LL-37 stimulation in ACS PBMCs. T effector cell response to LL-37 were either HLA dependent or independent as determined by blocking with monoclonal antibody to either Class-I HLA or Class-II HLA. Blocking of immune checkpoints PD-1 and CTLA-4 demonstrated the control of self-reactive T cell response to LL-37 was modulated predominantly by CTLA-4. Platelets from healthy controls down-modulated CD8+CD69+CD137+ T cell response to LL-37 in autologous PBMCs. CD8+CD69+CD137+ T cell AIM profile negatively correlated with platelet count in ACS patients.ConclusionsOur report demonstrates that the immune response to the autoantigen LL-37 in ACS patients is characterized specifically by CD8+CD69+CD137+ T cell AIM profile with persistent T cell activation and the generation of immunologic memory. The results provide potentially novel insight into mechanistic pathways of antigen-specific immune signaling in ACS

Enhanced Neointima Formation Following Arterial Injury in Immune Deficient Rag-1−/− Mice Is Attenuated by Adoptive Transfer of CD8+ T cells

T cells modulate neointima formation after arterial injury but the specific T cell population that is activated in response to arterial injury remains unknown. The objective of the study was to identify the T cell populations that are activated and modulate neointimal thickening after arterial injury in mice. Arterial injury in wild type C57Bl6 mice resulted in T cell activation characterized by increased CD4+CD44hi and CD8+CD44hi T cells in the lymph nodes and spleens. Splenic CD8+CD25+ T cells and CD8+CD28+ T cells, but not CD4+CD25+ and CD4+CD28+ T cells, were also significantly increased. Adoptive cell transfer of CD4+ or CD8+ T cells from donor CD8−/− or CD4−/− mice, respectively, to immune-deficient Rag-1−/− mice was performed to determine the T cell subtype that inhibits neointima formation after arterial injury. Rag-1−/− mice that received CD8+ T cells had significantly reduced neointima formation compared with Rag-1−/− mice without cell transfer. CD4+ T cell transfer did not reduce neointima formation. CD8+ T cells from CD4−/− mice had cytotoxic activity against syngeneic smooth muscle cells in vitro. The study shows that although both CD8+ T cells and CD4+ T cells are activated in response to arterial injury, adoptive cell transfer identifies CD8+ T cells as the specific and selective cell type involved in inhibiting neointima formation

CD8+ T Cells Mediate the Athero-Protective Effect of Immunization with an ApoB-100 Peptide

Immunization of hypercholesterolemic mice with selected apoB-100 peptide antigens reduces atherosclerosis but the precise immune mediators of athero-protection remain unclear. In this study we show that immunization of apoE (-/-) mice with p210, a 20 amino acid apoB-100 related peptide, reduced aortic atherosclerosis compared with PBS or adjuvant/carrier controls. Immunization with p210 activated CD8+ T cells, reduced dendritic cells (DC) at the site of immunization and within the plaque with an associated reduction in plaque macrophage immunoreactivity. Adoptive transfer of CD8+ T cells from p210 immunized mice recapitulated the athero-protective effect of p210 immunization in naïve, non-immunized mice. CD8+ T cells from p210 immunized mice developed a preferentially higher cytolytic response against p210-loaded dendritic cells in vitro. Although p210 immunization profoundly modulated DCs and cellular immune responses, it did not alter the efficacy of subsequent T cell dependent or independent immune response to other irrelevant antigens. Our data define, for the first time, a role for CD8+ T cells in mediating the athero-protective effects of apoB-100 related peptide immunization in apoE (-/-) mice

Inhibition of smooth muscle cell proliferation after balloon injury

Smooth muscle cell proliferation is an important part of the arterial response to injury Insulin like growth factor-I (IGF-I) is involved in regulation of cell proliferation and hypopituitarism is associated with decreased vessel wall response to injury. We investigated the role of vascular IGF-I in vessel wall response to injury. Further, restenosis after balloon angioplasty is decreased in patients with high levels of high density lipoproteins (HDL). We studied the effect of recombinant mutant apolipoprotein A I on arterial response to injury. In the rat model of endoluminal arterial balloon injury we have shown that within days after balloon injury the IGF-I mRNA level in the arterial wall increased several-fold, with concurrent increase in protein concentration and receptor down-regulation. The increased expression of IGF-I appeared to be primarily regulated locally as treatment with supraphysiological doses of growth hormone (GH) increased the IGF-I expression in the vessel wall only two-fold. Treatment of rats with the long-acting somatostatin analog octreotide prevented the injury induced upregulation of the IGF-I gene and was associated with dose dependent inhibition of SMC proliferation and neointimal thickening after balloon injury. The inhibitory effect of octreotide appeared to be IGF-I specific and regulated locally in the vessel wall. Octreotide in the doses used did not affect plasma GH, IGF-I and glucagon concentration or liver IGF-I expression. Transcription factor nuclear factor kB (NF-kB) plays a key role in inflammatory response and is also involved in SMC proliferation. Following balloon injury there was a transient two-fold increase in NF-kB nuclear binding. Treatment of rats with the oxygen radicals scavenger aspirin in high doses inhibited NF-kB nuclear binding and expression of NF-kB dependent intracellular adhesion molecule-l gene. These inhibitory effects of aspirin were associated with decreased SMC proliferation and neointimal thickening. Activation of many transcription factors is regulated by multiple phosphorylations. Treatment with octreotide increased the activity of tissue phosphatases and protein dephosphorylation and consequently inhibited NF-kB and fos/jun complex AP-I activation. Co-treatment of rats with okadaic acid, an inhibitor of tissue phosphatases, prevented the inhibitory effects of octreotide on NF-kB and AP-I activation. Rabbits on high-cholesterol chow treated with apolipoprotein mutant A-I Milano (apo A-I M) had less neointimal thickening after arterial balloon injury compared to untreated rabbits. The macrophage infiltration of the arterial wall was decreased in rabbits treated with apo A-I M suggesting that HDL mutant inhibits the accumulation of the proinflammatory cells in the vessel wall after balloon injury. The mechanism of the inhibitory effect did not appear to be related to the increased reverse cholesterol transport with the HDL mutant as the aortic wall cholesterol content was similar in treated and untreated rabbits. ISBN 91-628-2496-

Exploiting the vascular protective effects of high-density lipoprotein and its apolipoproteins - An idea whose time for testing is coming, Part I

Despite the benefits of currently available preventative and therapeutic interventions, atherosclerotic vascular disease continues to be a major cause of morbidity and mortality in much of the Western World. This emphasize,,, the need for additional preventive and therapeutic interventions exploiting new targets to compliment and augment the results of LDL lowering and other current strategies. One such potential target is HDL and its apolipoproteins, A large body of experimental evidence suggests that augmenting the levels and/or function of HDL and its apolipoproteins can have major vascular protective effects ranging from prevention to stabilization and regression, independent of total or non-HDL cholesterol levels. Therefore, we think that the time is ripe for the development and clinical testing of this new frontier in antiatherogenic strategy. In the present article, We will review the structure/function of HDL and explore means of enhancing the levels and/or function of HDL and its apolipoproteins for vascular protection