concanavalin-a and Heart-Failure

Little information is available to explain why beta-blockers are beneficial in certain patients with congestive heart failure (CHF). Since catecholamines alter immune function, we asked whether beta-blocker treatment leads to enhancement of immune function.. Fifteen patients with New York Heart Association class III-IV CHF secondary to dilated cardiomyopathy were titrated to a minimum dose of metoprolol 25 mg BID on a background therapy of digoxin, diuretic, and angiotensin-converting enzyme inhibitors. Cardiac and immunologic studies were done before and 6 months to 1 year after treatment. While these patients served as their own controls, an additional population of patients with heart failure was followed for a similar time period on traditional medications. A panel of seven delayed hypersensitivity skin tests were placed at 6- to 12-month intervals on the patient's forearm. Seventy percent of all CHF patients were anergic (unable to respond to more than 1 antigen). The 30% who could respond averaged 2.2 antigens. After treatment with metoprolol, only 20% remained anergic (P < .001). The 80% of responders averaged 4.2 antigens (P < .001). Additionally, patients treated with metoprolol had an increased percentage of T cells, natural killer cells, and increased interleukin-2 receptor density upon stimulation with concanavalin A. These changes correlated to increases in ejection fraction. Patients not treated with metoprolol remained anergic and had no beneficial immunologic changes.. It appears that patients with dilated cardiomyopathy who are treated with metoprolol have enhancement of cell-mediated immunity and improvement of T-cell function; these improvements are correlated to improvement in ejection fraction.

Topics: Adult; Aged; Cell Division; Concanavalin A; Heart Failure; Humans; Immune System; Lymphocyte Subsets; Metoprolol; Middle Aged; Skin Tests; Stroke Volume; Sympathetic Nervous System

Calsequestrin-2 (CSQ2) is a resident glycoprotein of junctional sarcoplasmic reticulum that functions in the regulation of SR Ca(2+) release. CSQ2 is biosynthesized in rough ER around cardiomyocyte nuclei and then traffics transversely across SR subcompartments. During biosynthesis, CSQ2 undergoes N-linked glycosylation and phosphorylation by protein kinase CK2. In mammalian heart, CSQ2 molecules subsequently undergo extensive mannose trimming by ER mannosidase(s), a posttranslational process that often regulates protein breakdown. We analyzed the intact purified CSQ2 from mongrel canine heart tissue by electrospray mass spectrometry. The average molecular mass of CSQ2 in normal mongrel dogs was 46,306 ± 41 Da, corresponding to glycan trimming of 3-5 mannoses, depending upon the phosphate content. We tested whether CSQ2 glycan structures would be altered in heart tissue from mongrel dogs induced into heart failure (HF) by two very different experimental treatments, rapid ventricular pacing or repeated coronary microembolizations. Similarly dramatic changes in mannose trimming were found in both types of induced HF, despite the different cardiomyopathies producing the failure. Unique to all samples analyzed from HF dog hearts, 20-40 % of all CSQ2 contained glycans that had minimal mannose trimming (Man9,8). Analyses of tissue samples showed decreases in CSQ2 protein levels per unit levels of mRNA for tachypaced heart tissue, also indicative of altered turnover. Quantitative immunofluorescence microscopy of frozen tissue sections suggested that no changes in CSQ2 levels occurred across the width of the cell. We conclude that altered processing of CSQ2 may be an adaptive response to the myocardium under stresses that are capable of inducing heart failure.

Topics: Animals; Atrial Natriuretic Factor; Calsequestrin; Carbohydrate Conformation; Carbohydrate Sequence; Concanavalin A; Disease Models, Animal; Dogs; Endoplasmic Reticulum, Rough; Gene Expression; Glycosylation; Heart Failure; Heart Ventricles; HEK293 Cells; Humans; Mannans; Molecular Weight; Natriuretic Peptide, Brain; Protein Binding; Protein Processing, Post-Translational; RNA, Messenger; Spectrometry, Mass, Electrospray Ionization

The objective of this study was to ascertain whether immune abnormalities were present in a group of patients with chronic stable heart failure at a time when sympathetic drive was not excessive. Elevated sympathetic tone not only plays an important role in the pathophysiologic characteristics of congestive heart failure but may also regulate certain aspects of immune function, which has been shown to be abnormal in patients with severe heart failure. Studies have indicated a high incidence of heterophil antibodies against constituents of the heart, the presence of antibody-mediated cytotoxicity against cultured heart cells, and a decrease in suppressor and natural killer-cell function in patients with idiopathic dilated cardiomyopathy. Lymphocytes were separated over a Ficoll-Hypaque gradient. Lymphocyte subtypes and well as interleukin-2 receptors were detected by means of mouse monoclonal antibodies conjugated with fluorescein or phycoerytherin, and immunofluorescence was measured with a flow cytometer. Mitogen proliferation was assessed by tritiated thymidine incorporation in the presence of either conconavalin A or tetanus toxoid. Serum was used in conjunction with iodine 125-labeled iodopindolol binding to rat cardiac membranes to attempt to detect beta-receptor antibodies. In patients with ischemic (n = 21) and idiopathic (n = 16) cardiomyopathy, the norepinephrine levels were modestly elevated (idiopathic = 482 +/- 70 pg/ml; ischemic = 501 +/- 45 pg/ml) compared with control subjects without heart disease (n = 10; norepinephrine = 252 +/- 70 pg/ml). We found no differences in the number and subtypes of circulating lymphocytes in the three groups, and there was no serum inhibition of beta-binding to rat cardiac membranes.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Chronic Disease; Concanavalin A; Heart Failure; Humans; Leukocyte Count; Lymphocyte Activation; Lymphocytes; Middle Aged; Receptors, Adrenergic, beta; Receptors, Interleukin-2; T-Lymphocytes; Tetanus Toxoid

Topics: Adolescent; Adult; Binding Sites; Cardiomyopathies; Cell Adhesion; Concanavalin A; Female; Heart Failure; Humans; Lymphocyte Culture Test, Mixed; Male; Middle Aged; T-Lymphocytes; Time Factors