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Biomedical subjects

C J Limas

Publications and source records attributed to C J Limas.

At least 19 recordsLinked to original sources
PubMed2003

Prognostic significance of soluble interleukin-2 receptor levels in patients with dilated cardiomyopathy.

BACKGROUND: Activation of T lymphocytes is thought to mediate myocardial dysfunction in dilated cardiomyopathy (CMP), probably through cytotoxic cytokines, but its value as a prognostic factor has not been evaluated. METHODS: For 2 years we prospectively followed 76 patients (65 males, 11 females, age 49 +/- 7 years) with CMP and New York Heart Association(NYHA) Class II-III heart failure; left ventricular (LV) function was assessed echocardiographically. Thirty-three patients (28 males, five females, age 52 +/- 6 years) with ischaemic heart disease (IHD) and similar NYHA and LV function characteristics were used as controls. Serum sIL-2R levels, peripheral blood lymphocyte proliferation (basal, + concanavalin A) and HLA-DQB1 genotyping was carried out in all patients. RESULTS: The CMP patients had increased sIL-2R levels (1259 +/- 130 pg mL-1) compared with the IHD patients (703 +/- 80 pg mL-1, P < 0.01, only 3 > 800 pg mL-1). In the CMP patients, there was a significant (r = +0.45, P= 0.04) correlation between sIL-2R and the LV end-diastolic diameter but not with the LV ejection fraction or NYHA Class. During the 24-month follow up, 17 of the CMP patients had an adverse clinical course (death, need for cardiac transplantation, or worsening heart failure). Of these, 14 (75%) had elevated (>or= 800 pg mL-1) sIL-2R levels (Group I) compared with only five (6%) with a stable clinical course (Group II). Neither [3H] thymidine incorporation into the peripheral blood lymphocytes nor the excess of HLA-DQB1-30 histidine homozygotes in the Group I patients (38% vs. 17%, P < 0.05) could predict the clinical outcome. CONCLUSION: Increased sIL-2R levels in CMP patients are an independent predictor of a more aggressive clinical course.

Cardiomyopathy, Dilated↗
PubMed2002

Hyperprolactinaemia in patients with heart failure: clinical and immunogenetic correlations.

BACKGROUND: Prolactin represents a stimulatory link between the neuroendocrine and immune systems, but its involvement in the neurohumoral adaptations to heart failure (HF) has not been explored. METHODS: We prospectively studied 55 patients (45 males, 10 females, age 48 +/- 7 years) with NYHA Class II/III HF due either to dilated cardiomyopathy (CMP) (n = 33) or ischemic heart disease (IHD) (n = 22). Serum prolactin levels were determined by radioimmunoassay, soluble interleukin-2 receptor (sIL-2R) levels by enzyme-linked immunoassay and HLA-DQ genotyping with PCR. Left ventricular ejection fraction (LVEF) and end-diastolic diameter (LVEDd) were assessed echocardiographically. RESULTS: Hyperprolactinaemia (17.3 +/- 4 ng mL-1 [Group I] vs. 4.64 +/- 2 ng mL-1 [Group II], P < 0.01) was found in 14 patients (8 with IHD, 6 with CMP). The distribution of HLA-DQB1 alleles was compared in the two groups and showed a significant increase in the frequency of *0301 (86% in Group I vs. 45% in Group II, P < 0.05). Histidine at position 30 of the HLA-DQB1 gene was found in 22% of Group II but in none of Group I patients. Furthermore, there was an inverse correlation between the presence of histidine at position 30 and the levels of serum prolactin. Both sIL-2R levels, a marker of T-cell activation, and concanavalin A-stimulated lymphocyte proliferation were lower in Group I patients (561 +/- 106 vs. 804 +/- 109 pg mL-1 and 20.8 +/- 4 vs. 37.3 +/- 5 cpmX103 [3H] thymidine, respectively). LVEF was significantly higher (32 +/- 5%) and LVEDd smaller (62.0 +/- 6 mm) in Group I compared to Group II (25 +/- 4% and 68.0 +/- 5 mm, respectively, P < 0.01) patients. CONCLUSION: Hyperprolactinaemia presents in 25% of patients with HF and may reflect decreased activation of T-lymphocytes associated with relatively preserved LV systolic function which is under immune-genetic control at the HLA-DQ locus.

Adult↗
PubMed1996

Autoimmunity in dilated cardiomyopathy and the major histocompatibility complex.

Autoimmune mechanisms are likely to participate in the pathogenesis of a subgroup of dilated cardiomyopathy. These mechanisms involve the elaboration of autoantibodies against cardiac proteins as well as abnormal lymphocyte regulation. The presence of autoantibodies against beta-adrenoceptors correlates with the human leukocyte antigen (HLA)-DR4/1 phenotypes and specific T-cell receptor haplotypes. In addition, histidine at position 36 of the HLA-DQ beta 1 gene is associated with the presence of clinically manifest dilated cardiomyopathy. Components of the major histocompatibility complex (MHC) may thus serve as markers for the propensity to develop immune-mediated myocardial damage.

Autoantibodies↗
PubMed1995

Soluble interleukin-2 receptor levels in patients with dilated cardiomyopathy. Correlation with disease severity and cardiac autoantibodies.

BACKGROUND: There is evidence that autoimmunity plays an important role in the initiation and progression of myocardial injury in dilated cardiomyopathy. Abnormalities of both cellular and humoral immunity have been described in this disease. Soluble interleukin-2 receptor (sIL-2R) levels in the serum reflect activation of T lymphocytes in the periphery or in tissues. The present study explored the possibility that activation of cellular immunity is frequent in patients with idiopathic dilated cardiomyopathy and may have functional consequences. METHODS AND RESULTS: Serum sIL-2R levels were determined with an enzyme-linked immunosorbent assay in 50 dilated cardiomyopathy patients, 30 patients with ischemic heart disease, and 22 normal control subjects. In addition, the presence of anti-beta-receptor and antimyosin antibodies was sought in the serum of cardiomyopathy patients. High sIL-2R levels (> 1400 pg/mL) were found in 38% of the dilated cardiomyopathy patients but only 6% of the ischemic heart disease patients. The group of sIL-2R-positive patients was characterized by higher average age, a higher percentage of women, and more severe disease (lower ejection fraction, higher left ventricular filling pressures, and lower cardiac output). Although the prevalence of cardiac autoantibodies did not correlate with the presence of high sIL-2R levels, higher titers of autoantibodies were found predominantly in the sIL-2R-positive group. CONCLUSIONS: T-lymphocyte activation, as reflected in elevated sIL-2R levels, is frequent in patients with dilated cardiomyopathy and is associated with more severe disease. Cellular and humoral immune activation may correlate with progression of the disease process.

Adult↗
PubMed1995

Possible involvement of the HLA-DQB1 gene in susceptibility and resistance to human dilated cardiomyopathy.

There is evidence that autoimmunity plays a role in the pathogenesis of dilated cardiomyopathy and that susceptibility to the disease is related to products of human leukocyte antigens (HLA) class II genes. We compared the distribution of HLA-DQA1 and -DQB1 alleles and haplotypes in 44 normal controls and 34 patients with idiopathic dilated cardiomyopathy patients. The distribution of two DQA1-DQB1 haplotypes (*0102-*0604 and *0102-*0501) were more frequent in the patients. Histidine at position 30 of the HLA-DQB1 gene was associated with disease (62% of patients compared to 36% of controls), whereas homozygosity for leucine at position 26 was more frequent in controls (36% vs 18% of patients). There was no correlation between HLA-DQA1-DQB1 haplotypes and the presence of anti-beta-receptor antibodies. These results suggest that the HLA-DQB1 gene is involved in the pathogenesis of human dilated cardiomyopathy.

Adult↗
PubMed1994

Anti-beta-receptor antibodies in familial cardiomyopathy: correlation with HLA-DR and HLA-DQ gene polymorphisms.

The presence of beta-receptor autoantibodies and their relationship to restriction fragment length polymorphisms of the human leukocyte antigen (HLA) class II genes were studied in 42 affected and unaffected members of a family with a heritable disorder of the conduction system and cardiac muscle. Antibodies were detected in 34% of all members (59% of affected and 22% of unaffected; p < 0.01). Significant differences between affected and unaffected individuals and between anti-beta-receptor antibody positive and negative individuals were noted in the prevalence of polymorphisms obtained with Taq I for the HLA-DR beta and HLA-DQ alpha genes. In affected individuals, there was a strong positive correlation between these polymorphisms and the presence of anti-beta-receptor antibodies. These results suggest that autoimmune mechanisms under the control of the class II genes play an important role in the pathogenesis of familial cardiomyopathy.

Arrhythmias, Cardiac↗
PubMed1992

Immune-mediated modulation of sarcoplasmic reticulum function in human dilated cardiomyopathy.

Calcium transport by the cardiac sarcoplasmic reticulum is depressed in human dilated cardiomyopathy, but the mechanisms involved are not clear. The possible involvement of immunological mechanisms was explored by evaluating the effect of sera from 49 patients with dilated cardiomyopathy on oxalate-facilitated Ca2+ uptake. In 14 of these patients, serum or IgG induced a time- and concentration-dependent decline (29 +/- 4% at 100-fold serum dilution) in Ca2+ transport. In 14 patients, autoantibodies against the beta 1-adrenoceptor were also demonstrated by a ligand binding inhibition assay. Serum from these patients inhibited the isoproterenol-mediated stimulation of Ca2+ uptake in permeabilized cardiac myocytes, but did not prevent the effect of protein kinase A. Anti-beta-receptor antibodies were present in 50% of the sera inhibiting Ca2+ uptake compared to 20% of those without inhibitory activity, (p less than 0.01). There was a strong correlation between the inhibition of sarcoplasmic reticulum Ca2+ transport and the HLA-DR4 phenotype (78% compared to 30% in patients with no inhibitory effect). These results suggest that immunological mechanisms play an important role in modifying sarcoplasmic reticulum function in about a third of the patients with detailed cardiomyopathy.

Adult↗
PubMed1992

T-cell receptor gene polymorphisms in familial cardiomyopathy: correlation with anti-beta-receptor autoantibodies.

Cardiac autoantibodies have been detected in a significant proportion of patients with dilated cardiomyopathy, but their relation to the pathogenesis of the disease remains unknown. This issue was examined in 41 members of an Ohio family with a heritable disorder of the cardiac conduction system and the myocardium. In 41.5% of all members studied, serum anti-beta-receptor antibodies were identified by a combination of techniques: ligand binding inhibition assay, enzyme-linked immunoassay of a beta 1-receptor peptide, and adenylate cyclase inhibition. The prevalence of autoantibodies was significantly higher (p < 0.01) in the affected (64.7%) than in the unaffected (25.0%) members. A 10.0 kb restriction fragment length polymorphism of the C beta region of the T-cell receptor gene was also overrepresented in affected males (60% versus 30% unaffected males, p < 0.01). In males, the presence of anti-beta-receptor antibodies was linked to the 10.0 kb C beta polymorphism. In affected males, a BlgII C alpha 2.14 kb polymorphism was also more frequent (62% versus 32% in unaffected, p < 0.01) and was linked to the presence of anti-beta-receptor antibodies. The distribution of haplotypes defined by V beta 8, C alpha, and C beta probes was significantly different between affected and unaffected (p < 0.04) and between antibody-positive and antibody-negative individuals. Since the major function of the T-cell receptor is the recognition of processed autoantigens, these results provide additional support for the role of autoimmunity in dilated cardiomyopathy.

Adult↗
PubMed1992

Assessment of immune modulation of beta-adrenergic pathways in human dilated cardiomyopathy: influence of methodologic factors.

Sera from patients with dilated cardiomyopathy contain autoantibodies modifying cardiac beta-adrenergic pathways. The influence of the methodology used to determine the prevalence of these antibodies was examined by comparing in 51 patients with idiopathic dilated cardiomyopathy the results of three assays: (1) isoproterenol-sensitive adenylate cyclase; (2) ligand binding inhibition; (3) enzyme-linked immunoassay (ELISA) of beta-receptor peptides. In 20% of the patients, all three tests gave positive results, while the concordance of the adenylate cyclase assay with either of the other two tests was 65%. ELISA was positive for a beta 1-receptor peptide corresponding to the second extracellular loop, but negative for a beta 2-receptor peptide. The results suggest that autoantibodies in dilated cardiomyopathy sera interact with several components of the beta-receptor-adenylate cyclase, and therefore a combination of methodologic approaches is needed to evaluate the prevalence and consequences of beta-receptor autoimmunity.

Adenylyl Cyclases↗
PubMed1992

HLA-DR antigen linkage of anti-beta receptor antibodies in idiopathic dilated and ischaemic cardiomyopathy.

OBJECTIVE: Immunological mechanisms have been implicated in the pathogenesis of human dilated cardiomyopathy. The presence of autoantibodies against the beta 1 adrenoceptor in a substantial proportion of patients with dilated cardiomyopathy has been described and an association between the HLA-DR4 phenotype and anti-beta receptor antibodies has been identified. The objective of the present study was to examine whether the presence of such antibodies in ischaemic cardiomyopathy was limited to specific HLA-DR phenotypes. DESIGN: The HLA-DR dependence of anti-beta receptor antibodies detected by a ligand binding inhibition assay in patients with dilated cardiomyopathy (n = 68) was compared with that in patients with ischaemic cardiomyopathy (n = 73). RESULTS: 38% of the patients with dilated cardiomyopathy and 22% of those with ischaemic cardiomyopathy had serum anti-beta receptor antibodies. In dilated cardiomyopathy, the presence of anti-beta receptor antibodies was linked to the HLA-DR4 phenotype (that is, 50% of patients with this phenotype were antibody positive) whereas, in those with ischaemic cardiomyopathy HLA-DR1 was over-represented (that is, 37% of the patients with the HLA-DR1 phenotype were antibody positive compared with 17% of the HLA-DR1 negative patients). In both disease entities, the HLA-DR3 phenotype was virtually absent in the anti-beta receptor antibody group. CONCLUSIONS: These results suggest that the presence of anti-beta receptor antibodies is under immune genetic control that may depend on the nature of the underlying disease process.

Adult↗
PubMed1991

Effect of antireceptor antibodies in dilated cardiomyopathy on the cycling of cardiac beta receptors.

A substantial proportion of patients with dilated cardiomyopathy have circulating autoantibodies directed against the cardiac beta-adrenoceptor. These antireceptor antibodies inhibit both ligand binding to membrane beta-receptors and isoproterenol-sensitive adenylate cyclase. The functional consequences of antibody-receptor interactions were further studied by examining their influence on beta-adrenoceptor cycling. Sera from eight patients with cardiomyopathy induced a loss of beta-receptors from the surface of cardiac myocytes consistent with internalization. This loss was inhibited by concanavalin A, suggesting that receptor sequestration preceded internalization but was unaffected by the cytoskeleton inhibitors colchicine and cytochalasin. In cell-free preparations, serum-induced desensitization of beta-receptors was prevented by heparin but not the inhibitor of protein kinase A; this is consistent with a requirement for receptor phosphorylation by the beta-receptor kinase. In contrast to isoproterenol-mediated endocytosis, beta-receptors internalized under the influence of cardiomyopathic sera do not recycle to the plasma membrane. These results indicate that antireceptor antibodies in human dilated cardiomyopathy induced downregulation by interfering at several steps in the cycling of beta-receptors. These effects would contribute to the reported decline in beta-receptor responsiveness in cardiomyopathic myocardium.

Adult↗
PubMed1991

Beta-adrenoceptor antibodies and genetics in dilated cardiomyopathy--an overview and review.

Autoantibodies against the cardiac beta-adrenoceptor are present in 30-40% of patients with idiopathic dilated cardiomyopathy and can be detected using ligand binding inhibition, immunoprecipitation or immunoblotting. The functional consequences of the antibody-receptor interactions are two-fold: (a) in isolated cardiac myocytes, diluted sera from cardiomyopathy patients induce internalization of the beta-receptors which are subsequently degraded intracellularly; (b) in membrane preparations, anti-receptor antibodies inhibit selectively the activity of isoproterenol-sensitive adenylate cyclase. The presence of anti-receptor antibodies is strongly linked to the HLA-DR4 phenotype: 72% of the HLA-DR4 patients in our series had anti-beta-receptor antibodies compared with 22% of the HLA-DR4-negative patients (most of which typed as HLA-DR1). Conversely, 67% of the antibody-positive patients typed as HLA-DR4, compared with only 10% of the antibody-negative patients. These results indicate the presence, in a subset of cardiomyopathy patients, of immunogenetical factors which may modulate myocardial beta-adrenoceptor function.

Autoantibodies↗
PubMed1991

Disparate effects of colchicine on thyroxine-induced cardiac hypertrophy and adrenoceptor changes.

Short-term (5 days) administration of L-thyroxine (0.1 mg/kg i.p. daily) to adult Sprague-Dawley rats induces a modest degree of cardiac hypertrophy (22% increase in heart weight/body weight ratios) and directionally opposite changes in cardiac adrenoceptors (24% increase in beta-adrenoceptors and 20% decline in alpha 1-adrenoceptors). Pretreatment with colchicine did not affect the ability of L-thyroxine to induce cardiac hypertrophy but prevented its effects on both beta- and alpha 1-adrenoceptors. These results suggest a selective involvement of microtubules in the action of thyroid hormones on the expression of cardiac adrenoceptor genes.

Animals↗
PubMed1990

Anti-beta-receptor antibodies in human dilated cardiomyopathy and correlation with HLA-DR antigens.

The mechanisms responsible for the decline in the density of beta-adrenoceptors in the failing myocardium have not been adequately defined. It is a possibility that the nature of the process leading to heart failure may determine, in large part, the pathogenesis of this decline. Sera of some patients with dilated cardiomyopathy contain antibodies directed against the beta-adrenoceptor, as judged by ligand binding inhibition, immunoprecipitation and immunoblotting assays. Because deranged immune function is thought to play a role in dilated cardiomyopathy, immunogenetic markers of the propensity to develop anti-beta-receptor antibodies were sought. The prevalence of HLA-DR4 was significantly higher in dilated cardiomyopathy patients (40 vs 24% in 511 normal subjects, pc less than 0.001). In contrast, no association was found between HLA phenotypes and alcoholic cardiomyopathy. Furthermore, 72% (13 of 18) of the HLA-DR4 dilated cardiomyopathy patients had anti-beta-receptor antibodies compared to 22% (7 of 33) HLA-DR4-negative patients; in the latter, presence of antibody was linked to the HLA-DR1 phenotype. Conversely, 67% (15 of 23) of the antibody-positive patients were typed as HLA-DR4 compared to only 10% of the antibody-negative patients. Interestingly, none of the 23 antibody-positive patients were typed as HLA-DR3 while 37% of the antibody-negative did. Only 25% of alcoholic cardiomyopathy patients had anti-beta-receptor antibodies and no preponderant HLA association could be demonstrated. These results suggest that the presence of anti-beta-receptor antibodies in patients with idiopathic dilated cardiomyopathy may be under the control of the major histocompatibility locus.

Autoantibodies↗
PubMed1990

Influence of anti-beta-receptor antibodies on cardiac adenylate cyclase in patients with idiopathic dilated cardiomyopathy.

Autoantibodies against the cardiac beta 1-adrenoceptor are present in the sera of patients with idiopathic dilated cardiomyopathy and may modulate the responsiveness of cardiac beta-adrenergic pathways to agonists. The regulation of cardiac adenylate cyclase activity by autoantibodies was examined in 50 patients with dilated cardiomyopathy. Inhibition of isoproterenol-sensitive adenylate cyclase activity could be demonstrated by serum dilutions or IgG in 52% (26 of 50) of the patients; basal and NaF-stimulated activities, in contrast, were unaffected. In 14 patients, both ligand binding to beta-receptor and isoproterenol-sensitive adenylate cyclase activity were inhibited by 100-fold serum dilutions. Pretreatment of cardiac membranes with pertussis toxin did not affect inhibition of adenylate cyclase indicating that the effect of sera does not depend on Gi. The immunogenetic control of antireceptor antibodies was examined by comparing the distribution of HLA antigens in antibody-positive and antibody-negative patients. HLA-DR4 and HLA-DR1 were strongly associated with antibodies inhibiting ligand binding and adenylate cyclase activity (71% of patients with such antibodies typed as either DR4 or DR1). Conversely 58% of patients with HLA-DR4 and 71% of patients with HLA-DR1 antibodies showed inhibition of adenylate cyclase activity compared to 46% of those who lacked both HLA-DR4 and HLA-DR1 antibodies. These results strongly suggest that cardiac beta-adrenergic receptors and adenylate cyclase activity in dilated cardiomyopathy can be modulated by circulating autoantibodies, the presence of which is under the control of the major histocompatibility complex.

Adenylyl Cyclase Inhibitors↗