RESUMEN
We have previously demonstrated that bacterial lipopolysaccharide (LPS) is capable of promoting Coxsackie B3 (CB3)-induced myocarditis in genetically resistant B10.A mice. Because LPS is known to increase production of various cytokines, we tested CB3-infected, LPS-treated mice for the presence of interleukin 1 (IL-1) and tumor necrosis factor (TNF). We found significantly increased amounts of both cytokines in the sera of CB3/LPS-treated mice compared with animals treated only with LPS. We also found immunohistochemical evidence for local production of these cytokines in the cardiac tissue of CB3/LPS-treated mice. Treatment with IL-1 or TNF alone promoted CB3-induced autoimmune myocarditis in resistant B10.A mice. Myocarditis was also observed when uninfected mice were immunized with syngeneic heart extract in the presence of IL-1 or TNF.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Infecciones por Coxsackievirus/inmunología , Interleucina-1/metabolismo , Miocarditis/microbiología , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Lipopolisacáridos/administración & dosificación , Ratones , Ratones Endogámicos C57BL , Miocarditis/inmunología , Miocarditis/patología , Miocardio/inmunología , Miocardio/patologíaRESUMEN
Nitric oxide (NO) is a radical molecule that not only serves as a vasodilator and neurotransmitter but also acts as a cytotoxic effector molecule of the immune system. The inducible enzyme making NO, inducible NO synthase (iNOS), is transcriptionally activated by IFN-gamma and TNF-alpha, cytokines which are produced during viral infection. We show that iNOS is induced in mice infected with the Coxsackie B3 virus. Macrophages expressing iNOS are identified in the hearts and spleens of infected animals with an antibody raised against iNOS. Infected mice have increased titers of virus and a higher mortality when fed NOS inhibitors. Thus, viral infection induces iNOS in vivo, and NO inhibits viral replication. NO is a novel, nonspecific immune defense against viruses in vivo.
Asunto(s)
Infecciones por Coxsackievirus/fisiopatología , Enterovirus Humano B/fisiología , Miocarditis/fisiopatología , Miocarditis/virología , Óxido Nítrico Sintasa/biosíntesis , Óxido Nítrico/fisiología , Replicación Viral , Secuencia de Aminoácidos , Animales , Anticuerpos , Arginina/análogos & derivados , Arginina/toxicidad , Línea Celular , Células Cultivadas , Infecciones por Coxsackievirus/inmunología , Enterovirus Humano B/efectos de los fármacos , Inducción Enzimática , Inhibidores Enzimáticos/toxicidad , Inmunohistoquímica , Isoenzimas/análisis , Isoenzimas/biosíntesis , Activación de Macrófagos , Macrófagos/enzimología , Macrófagos/inmunología , Ratones , Ratones Endogámicos , Datos de Secuencia Molecular , Miocarditis/inmunología , Miocardio/enzimología , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintasa/análisis , Óxido Nítrico Sintasa/antagonistas & inhibidores , Fragmentos de Péptidos/síntesis química , Fragmentos de Péptidos/inmunología , Conejos , Bazo/enzimología , Transcripción Genética/efectos de los fármacos , Replicación Viral/efectos de los fármacos , omega-N-MetilargininaRESUMEN
Group B coxsackieviruses are the most frequent causative agents in human viral myocarditis. Susceptibility to viral infections varies widely among individuals. In the mouse, coxsackievirus B3 also causes myocarditis. The differential susceptibility of different inbred strains of mice to coxsackie B3-induced myocarditis also appears to be under genetic control. This study details the histopathology of coxsackie B3 myocarditis in six different inbred strains of mice for the first 45 days after coxsackie B3 infection. These strains differ either in the haplotypes of their major histocompatibility complex or in their background genome. During the first 7 days after coxsackie B3 infection, there are dramatic differences among strains with respect to prevalence and severity of myocarditis. Focal zones of myocyte necrosis involving polymorphonuclear leukocytes as well as contraction band injury appear to be the early manifestations of direct viral injury. Four of the six strains, though, continue to show myocardial inflammation after day 9. This late phase myocarditis is characterized by the emergence of mononuclear cells within healing foci of myocyte necrosis as well as a distinctive diffuse interstitial pattern of myocarditis. The strains that develop this late ongoing myocardial inflammation frequently produce heart-specific autoantibodies. Thus the pathologic features of murine coxsackie B3 myocarditis change over the course of the illness, and genetic susceptibility to both early and late phase myocarditis differs markedly among various mouse strains.
Asunto(s)
Infecciones por Coxsackievirus/veterinaria , Ratones Endogámicos/genética , Ratones , Miocarditis/veterinaria , Enfermedades de los Roedores/patología , Animales , Enterovirus Humano B , Femenino , Miocarditis/etiología , Miocarditis/mortalidad , Miocarditis/patología , Enfermedades de los Roedores/etiología , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
Heart-reactive antibodies are commonly observed in patients with myocarditis or cardiomyopathy. Such antibodies may be important in the pathogenesis of these disorders, yet the specific antigens recognized have not been studied systematically. This report characterizes circulating heart autoantibodies from patients with myocarditis (n = 17) or idiopathic cardiomyopathy (n = 71) and from healthy volunteers (n = 15). Indirect immunofluorescence demonstrated that high titer (greater than or equal to 1:20) immunoglobulin G (IgG) antibody activity occurred in 59% of the myocarditis samples, 20% of the cardiomyopathy samples and none of the normal samples. All samples were tested by Western immunoblotting for IgG activity against a normal human heart extract. The number of antigens recognized by each sample was enumerated and the molecular weight of each antigen estimated; the prevalence of reactivity against antigens in selected molecular weight classes was determined. There was no difference in the mean number of heart antigens recognized by serum from each group. For most weight classes, prevalence either did not differ significantly among the various groups or subgroups or was greatest among samples from healthy volunteers. Prevalence of reactivity with 190 to 199 kilodalton (kd) antigens was greatest (p less than 0.05) among low titer serum samples from patients with myocarditis. High titer cardiomyopathy serum differed from normal serum by an increased (p less than 0.05) prevalence of antibodies to 40 to 49 and 100 to 109 kd antigens. These results suggest that western immunostaining may ultimately contribute substantively to identifying patients with myocarditis or cardiomyopathy.
Asunto(s)
Anticuerpos/sangre , Cardiopatías/inmunología , Inmunoglobulina G/análisis , Miocarditis/inmunología , Adolescente , Adulto , Anciano , Western Blotting , Niño , Femenino , Técnica del Anticuerpo Fluorescente , Cardiopatías/sangre , Humanos , Masculino , Persona de Mediana Edad , Peso MolecularRESUMEN
OBJECTIVES: We studied canine coronary arterial vasoreactivity after occlusion and reperfusion to examine whether reduced flow or pressure contributed to the abnormalities observed. BACKGROUND: Ischemia and reperfusion alter endothelial and myocardial function. Causative factors may include altered flow, complement activation or free radical production by endothelial or white blood cells after reoxygenation and neutrophil activation. METHODS: The coronary arteries of anesthetized, open chest dogs were subjected to 90-min occlusion +/- 2 h of reperfusion. The effect of reperfusion on arterial responses to intracoronary acetylcholine, nitroprusside and phenylephrine was studied using in vivo ultrasound. Arterial segments were also harvested, perfused ex vivo with cell-free buffer and exposed to potassium chloride, nitroprusside, acetylcholine and bradykinin. The effect of ex vivo flow cessation with or without maintained intralumen pressure was also studied. RESULTS: Results are expressed as mean value +/- SEM. In vivo arterial cross-sectional area increased during infusion with acetylcholine (10(-5) mol/liter [18.5 +/- 9%]) and nitroprusside (10(-5) mol/liter [22.5 +/- 10%]) and decreased with phenylephrine (10(-5) mol/liter [7.6 +/- 7%]). After reperfusion, acetylcholine caused 13.5 +/- 9% vasoconstriction. Nitroprusside and phenylephrine responses were unchanged. Reperfused arterial segments also showed impaired vasodilation in response to 10(-6) mol/liter of acetylcholine (10.6 +/- 5.1% vs. 47.1 +/- 4.9% in control vessels) and 10(-8) mol/liter of bradykinin (4.4 +/- 6.7% vs. 27.9 +/- 8% in control vessels). Ex vivo flow cessation impaired acetylcholine-mediated vasodilation, but this abnormality was prevented when high intralumen pressure was maintained during the no-flow period. CONCLUSIONS: Reduction in flow and intralumen pressure contribute to the impaired acetylcholine-mediated vasodilation seen after coronary occlusion. This is prevented by maintaining high intralumen pressure during the no-flow period, suggesting that hemodynamic forces may change endothelial function independent of circulating complement or blood cell elements.
Asunto(s)
Vasos Coronarios/fisiología , Endotelio Vascular/fisiología , Isquemia Miocárdica/fisiopatología , Reperfusión Miocárdica , Vasodilatación , Acetilcolina/farmacología , Animales , Vasos Coronarios/diagnóstico por imagen , Vasos Coronarios/efectos de los fármacos , Perros , Femenino , Hemodinámica , Masculino , Nitroprusiato/farmacología , Pericardio/fisiología , Fenilefrina/farmacología , UltrasonografíaRESUMEN
Histologic evidence of myocarditis was demonstrated in 35 of 348 patients submitted to endomyocardial biopsy over 5 years. Analysis of the histologic findings and clinical course of these patients resulted in a new clinicopathologic classification of myocarditis in which four distinct subgroups are identified. Patients with fulminant myocarditis become acutely ill after a distinct viral prodrome, have severe cardiovascular compromise, multiple foci of active myocarditis by histologic study and ventricular dysfunction that either resolves spontaneously or results in death. Patients with acute, chronic active and chronic persistent myocarditis have a less distinct onset of illness. Patients with acute myocarditis present with established ventricular dysfunction and may respond to immunosuppressive therapy or their condition may progress to dilated cardiomyopathy. Those with chronic active myocarditis initially respond to immunosuppressive therapy, but they have clinical and histologic relapses and develop ventricular dysfunction associated with chronic inflammatory changes including giant cells on histologic study. Chronic persistent myocarditis is characterized by a persistent histologic infiltrate, often with foci of myocyte necrosis but without ventricular dysfunction despite other cardiovascular symptoms such as chest pain or palpitation.
Asunto(s)
Miocarditis/patología , Enfermedad Aguda , Adulto , Anciano , Baltimore/epidemiología , Biopsia , Cateterismo Cardíaco , Enfermedad Crónica , Ecocardiografía , Femenino , Fibrosis , Células Gigantes/patología , Hospitales Universitarios , Humanos , Masculino , Persona de Mediana Edad , Miocarditis/clasificación , Miocarditis/epidemiología , Necrosis , FotomicrografíaRESUMEN
The histologic diagnosis of active myocarditis is frequently difficult to establish. A nonhistologic marker of immune activation would be clinically useful in identifying cases of immune-mediated myocarditis. A viral etiology with subsequent autoimmunity to cardiac antigens has been implicated in human myocarditis. Because autoimmunity and viral disease are commonly associated with increased expression of major histocompatibility complex (MHC) antigens on targeted tissue, we examined endomyocardial biopsy samples from patients with active myocarditis for abnormal levels of MHC antigen expression. Thirteen patients with active myocarditis and eight control patients with other well-defined cardiac diagnoses (coronary disease, amyloidosis or neoplasm) were studied. A sensitive radioimmunoassay was developed that utilized monoclonal antibodies to human MHC class I and class II antigens in order to quantitate the expression of both of these antigens within each biopsy. Abnormal MHC class I and class II antigen expression was present in 11 of 13 myocarditis specimens and 1 of 8 control samples (specificity 88%, sensitivity 84.6%). Active myocarditis samples had approximately a 10-fold increase in MHC class I and class II expression. Immunoperoxidase staining localized abnormal MHC expression primarily within microvascular endothelium and along myocyte surfaces (11 of 13). This study is the first to demonstrate a marked increase in major histocompatibility complex antigen expression within the myocardium of patients with active myocarditis. The identification of abnormal histocompatibility antigen expression within an endomyocardial biopsy may prove a useful adjunct to the histologic diagnosis of myocarditis.
Asunto(s)
Antígenos HLA/análisis , Antígenos HLA-D/análisis , Miocarditis/diagnóstico , Adulto , Anciano , Anticuerpos Monoclonales , Autoanticuerpos/análisis , Biomarcadores/análisis , Endotelio Vascular/inmunología , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Persona de Mediana Edad , Miocarditis/inmunología , Valor Predictivo de las Pruebas , RadioinmunoensayoRESUMEN
OBJECTIVES: The purpose of this study was to characterize the histologic and immunopathologic results of 37 endomyocardial biopsy samples from patients infected with human immunodeficiency virus type 1 (HIV-1) who were evaluated for unexplained global left ventricular dysfunction. BACKGROUND: Recent studies have identified a growing number of patients infected with HIV-1 who develop unexplained left ventricular dysfunction and congestive heart failure. Myocarditis has been confirmed at autopsy in small numbers of such patients, although a pathogenic opportunistic infectious agent can rarely be identified. METHODS: All patients had moderate to severe global left ventricular hypokinesia on two-dimensional echocardiography. Endomyocardial biopsy samples were evaluated by standard histologic studies, immunoperoxidase staining and in situ hybridization for cytomegalovirus and HIV-1 gene sequences. RESULTS: Twenty-eight patients presented with New York Heart Association functional class III or IV congestive heart failure. Four patients had myocarditis secondary to known etiologies (opportunistic infection n = 2; drug-induced hypersensitivity myocarditis n = 2). Of the remaining 33 samples, 17 (51%) showed histologic evidence of idiopathic active or borderline myocarditis. Immunohistologic findings revealed induced expression of major histocompatibility class I antigen on myocytes and increased numbers of infiltrating CD8+ T lymphocytes. Specific hybridization within myocytes was observed in 5 of 33 samples with the HIV-1 antisense riboprobe and in 16 of 33 samples with the cytomegalovirus immediate early (IE-2) antisense riboprobe. All but one patient with specific myocyte hybridization presented with congestive heart failure; all patients had myocarditis and CD4+ cell counts < 100/mm3. CONCLUSIONS: This study demonstrates that cardiotropic virus infection and myocarditis may be important in the pathogenesis of symptomatic HIV-associated cardiomyopathy.
Asunto(s)
Infecciones Oportunistas Relacionadas con el SIDA/complicaciones , Infecciones por Citomegalovirus/complicaciones , Infecciones por VIH/complicaciones , Miocarditis/complicaciones , Disfunción Ventricular Izquierda/complicaciones , Infecciones Oportunistas Relacionadas con el SIDA/patología , Adulto , Biopsia , Estudios de Cohortes , Infecciones por Citomegalovirus/patología , Ecocardiografía , Femenino , Infecciones por VIH/patología , Humanos , Inmunohistoquímica , Hibridación in Situ , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Miocarditis/patología , Miocardio/patología , Estudios Prospectivos , Disfunción Ventricular Izquierda/patologíaRESUMEN
To identify specific histologic abnormalities that could predict early cardiac rejection before the development of myocyte necrosis, 167 consecutive endomyocardial biopsy samples from 18 cardiac transplant recipients were retrospectively analyzed and 17 histologic variables were semiquantitatively graded from 0 to 3. Forty-five biopsy samples contained foci of myocyte necrosis and were labeled Rejectors. The two samples immediately preceding Rejector biopsies were labeled Predictors (n = 44). All remaining samples were labeled Others (n = 78). Endocardial and interstitial infiltrates, interstitial mononuclear cells, pyroninophilic mononuclear cells, polymorphonuclear leukocytes and other cells (eosinophils and plasma cells) were significantly increased in graded severity in Rejector biopsy samples as compared with Predictors or Others (p less than 0.001, ANOVA testing). These variables cannot distinguish Predictor biopsy specimens from Others. On the other hand, interstitial edema, perivascular karyorrhexis and perivascular infiltrate with intermyocyte extension are histologic abnormalities that can distinguish Predictor biopsy samples from Others (p less than 0.001, ANOVA testing). Multiple logistic regression analysis indicates that the relative risk of developing myocyte necrosis when a biopsy sample contains interstitial edema is 8.1. With perivascular infiltrate with intermyocyte extension in addition, the relative risk is 41.4. In summary, three histologic abnormalities have been identified that help predict the future development of myocyte necrosis within the next two endomyocardial biopsies. Biopsy specimens with these abnormalities probably represent early cardiac rejection before the development of myocyte necrosis.
Asunto(s)
Rechazo de Injerto , Trasplante de Corazón , Miocardio/patología , Biopsia , Eritrocitos/patología , Humanos , Monocitos/patología , Necrosis/patología , Neutrófilos/patología , Probabilidad , Estudios RetrospectivosRESUMEN
OBJECTIVE: Recent clinical and echocardiographic studies have identified dilated cardiomyopathy in 10-20% of HIV-infected adults. The purpose of this study was to determine the role of cardiotropic cytomegalovirus (CMV) infection in the development of HIV-associated cardiomyopathy. DESIGN: We generated sense and antisense digoxigenin-labeled riboprobes derived from the CMV immediate-early (IE) and delayed-early (DE) genes and applied them retrospectively to endomyocardial biopsy samples and control autopsy cardiac samples from HIV-infected patients. SETTING: Tertiary care, referral hospital. PATIENTS: Twelve consecutive HIV-infected patients with global left ventricular hypokinesis demonstrated on two-dimensional echocardiography; eight randomly selected control autopsy cardiac samples from HIV-infected patients without cardiac disease during life. MEASUREMENTS AND MAIN RESULTS: Of the 12 endomyocardial biopsy specimens, six (50%) were found to have specific myocyte nuclear and perinuclear hybridization for transcripts of the CMV IE gene, consistent with non-permissive or latent infection. Similar patterns were not found in any of the eight autopsy control samples. All six patients presented with unexplained congestive heart failure and had CD4 counts less than 100 x 10(6)/l; all six biopsy samples had immunohistochemical evidence of increased myocardial major histocompatibility complex (MHC) class I expression, a finding typical of non-HIV myocarditis. None of the endomyocardial biopsy samples had characteristic CMV inclusions and no specific hybridization was noted with the DE gene riboprobe, suggesting that no active viral DNA replication was present. Only two of the six patients with myocyte hybridization with the IE riboprobe had clinical evidence of solid organ infection with CMV at the time of cardiovascular presentation. CONCLUSIONS: This study is the first to demonstrate the expression of the IE gene of CMV within myocytes from HIV-infected patients with cardiomyopathy, suggesting a non-permissive infection of myocytes without classical intranuclear inclusions. Myocyte infection may be necessary to trigger cellular and humoral-mediated cardiac injury and may be best identified using in situ hybridization techniques.
Asunto(s)
Cardiomiopatías/microbiología , Citomegalovirus/aislamiento & purificación , Infecciones por VIH/microbiología , Adulto , Citomegalovirus/genética , Femenino , Genes Virales/genética , Humanos , Complejo Mayor de Histocompatibilidad/genética , Masculino , Persona de Mediana Edad , Hibridación de Ácido Nucleico , ARN Mensajero/análisis , ARN Viral/análisisRESUMEN
A 53-year-old man with occlusion of the proximal left anterior descending coronary artery received intravenous tissue plasminogen activator, and reperfusion was achieved within four and a half hours from the onset of chest pain. Recurrence of electrocardiographic ST segment elevation without attendant chest pain heralded reocclusion in the first hour after thrombolysis, which was successfully treated. After a stable course, post-infarction refractory cardiogenic shock developed on day 4, and autopsy demonstrated a massive (more than 100 cm2) hemorrhagic infarct. Several features of this case underscore the potential of coronary thrombolysis to cause significant reperfusion injury.
Asunto(s)
Cardiopatías/complicaciones , Hemorragia/etiología , Infarto del Miocardio/patología , Niño , Cardiopatías/tratamiento farmacológico , Humanos , Persona de Mediana Edad , Infarto del Miocardio/complicaciones , Infarto del Miocardio/tratamiento farmacológico , Activador de Tejido Plasminógeno/efectos adversos , Activador de Tejido Plasminógeno/uso terapéuticoRESUMEN
Combination CsA with corticosteroids is the most commonly used maintenance immunosuppressive regimen after cardiac transplantation, although their high-toxicity profiles frequently limit their clinical benefit. Immunosuppressive agents that would act synergistically with CsA but without the toxicity profile of corticosteroids would be clinically useful. Thalidomide was removed from the market due to its teratogenic effects, although it has known immunomodulatory activity. The purpose of this study was (1) to determine whether maintenance immunosuppression with thalidomide and subtherapeutic doses of CsA can help prevent rat cardiac allograft rejection; and (2) to compare its synergism with CsA to the commonly used corticosteroid, methylprednisolone. ACI-LEW allografts were all treated with subtherapeutic doses of CsA (10 mg/g/day, s.c.) for 4 days. When CsA was then discontinued, severe rejection developed by posttransplant day 14. Group 1 received CsA alone. Group 2 received in addition oral thalidomide 100 mg/day for 14 days. Groups 3, 4, and 5 received CsA and methylprednisolone (low dose: 0.2 mg/kg/day s.c.; moderate dose: 2.0 mg/kg/day s.c.; and high dose: 20 mg/kg/day s.c. Twelve histologic parameters of rejection were semiquantitatively graded 0-4, and total pathology scores were determined. The combination of thalidomide and subtherapeutic CsA significantly reduced the severity of myocardial necrosis, interstitial inflammation, interstitial edema, and the total pathology score. Thalidomide was found to be equally as effective as low-, moderate-, and high-dose methylprednisolone. The results of this study suggest the potential clinical role of CsA and thalidomide in maintenance immunosuppressive regimens, thereby avoiding the use of corticosteroids.
Asunto(s)
Ciclosporinas/administración & dosificación , Rechazo de Injerto/efectos de los fármacos , Trasplante de Corazón , Metilprednisolona/administración & dosificación , Talidomida/administración & dosificación , Animales , Quimioterapia Combinada , Terapia de Inmunosupresión , Masculino , Ratas , Ratas Endogámicas Lew , Trasplante HomólogoRESUMEN
During acute rejection, CD4 and CD8 T cells infiltrate the myocardium and cause myocyte death and dropout. CD4 and CD8 cells use a number of cytotoxic mechanisms, including fas-fas ligand interactions, which lead to apoptotic death. Since fas is expressed on myocytes, we investigated endomyocardial biopsy specimens from cardiac transplant patients to determine whether apoptosis is one of the mechanisms of cell death in acute rejection. Serial sections of individual endomyocardial biopsy specimens from patients histologically diagnosed as having grade 3A rejection (n=22 biopsy specimens), biopsy specimens showing a typical "Quilty effect" (n=10), and specimens with concurrent grade 3A rejection and the Quilty effect (n=6) were evaluated using the C-terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) technique for frequency of apoptosis in myocytes and mononuclear cell infiltrates. None of the examined sections showed detectable evidence of apoptotic myocytes, even within regions clearly showing myocyte damage. Of interest was our consistent finding that 85-98% of mononuclear cell infiltrates within biopsy specimens scored as having grade 3A rejection had undergone apoptosis. In marked contrast, 9 of the 10 specimens with Quilty lesions showed <5% apoptotic mononuclear cells in the endomyocardial infiltrates. Of further interest was our finding of 85-98% apoptotic mononuclear cell infiltrates within Quilty lesions associated with biopsy specimens scored as having grade 3A rejection. The frequency of apoptotic cells determined by the TUNEL technique was confirmed by histological examination of the morphology of the cells and with a technique that involves detection of c-jun. These results prompt a note of caution in the interpretation of data on the phenotype, cytokine profile, Vbeta T cell receptor repertoire, and donor specificity of mononuclear cells cultured and propagated from such cardiac biopsy specimens. The possible reasons for apoptosis of graft-infiltrating mononuclear cells are discussed.
Asunto(s)
Apoptosis , Trasplante de Corazón/patología , Monocitos/patología , Adulto , Anciano , Biopsia , Biotina/química , Células Cultivadas , Nucleótidos de Desoxiuracil/química , Femenino , Rechazo de Injerto/patología , Trasplante de Corazón/inmunología , Humanos , Masculino , Persona de Mediana Edad , Miocardio/citología , Trasplante Homólogo/inmunología , Trasplante Homólogo/patologíaRESUMEN
Hyperacute rejection results in rapid destruction of a discordant cardiac xenograft and is characterized by antibody deposition, complement activation, and platelet aggregation. The importance of neutrophils is unclear. Complement inhibition prolongs discordant cardiac xenograft survival. The purpose of this experiment was to determine the relative roles of complement and neutrophils. Selective inhibition of complement and neutrophil adhesion was used in a guinea pig-to-Lewis rat cardiac heterotopic xenotransplant model. NPC 15669 (N-[9H-(2,7-dimethylfluorenyl-9-methoxy)carbonyl]-L-leucine), a member of a new class of antiinflammatory agents termed leumedins, specifically prevents recruitment of neutrophils at inflammatory foci by inhibiting upregulation of the CD11b/CD18 adhesion molecule. Soluble complement receptor type 1 (sCR1, BRL 55730) is a potent inhibitor of the alternative and classical complement pathways. Group I (n = 13) received saline vehicle i.v. Group II (n = 15) was treated with NPC 15669 (10 mg/kg i.v. bolus) prior to reperfusion. Group III (n = 13) was treated with sCR1 (20 mg/kg i.v. bolus) prior to reperfusion. Group IV (n = 13) received both NPC 15669 and sCR1. Two xenografts were harvested at each interval time point (Groups I and II, 1, 2, 4, and 6 min; and Groups III and IV, 6, 15, 30, and 60 min). The remainder were followed to cessation of graft function. Graft survival was significantly increased in group IV and group III-375 +/- 13.4 min (mean +/- SD) and 112 +/- 29.4, respectively (P < .05), compared with 9.9 +/- 6.3 in group II and 8.7 +/- 4.9 in group I. Extreme interstitial hemorrhage and edema and contraction band injury were present in group I-III animals at end-stage, and neutrophil infiltration in group III. In group IV grafts, there was a decrease in these parameters despite the longer survival time, and at end-stage rejection the cellular infiltrate was primarily mononuclear. This study demonstrates that complement is an important mediator in early xenograft HYP injury. Combined treatment with NPC 15669 and sCR1 results in reduced histologic injury at all time points and longer graft survival than with sCR1 alone. These results suggest that neutrophil and complement activation play synergistic roles in the pathogenesis of xenograft hyperacute rejection. Neutrophil inhibition may prove to be an important component of multimodality therapy for hyperacute rejection, particularly in less-discordant transplants.
Asunto(s)
Proteínas Inactivadoras de Complemento/farmacología , Trasplante de Corazón/inmunología , Neutrófilos/citología , Trasplante Heterólogo/inmunología , Animales , Antiinflamatorios no Esteroideos/farmacología , Adhesión Celular , Rechazo de Injerto/prevención & control , Supervivencia de Injerto/efectos de los fármacos , Cobayas , Leucina/análogos & derivados , Leucina/farmacología , Ratas , Ratas Endogámicas Lew , Receptores de Complemento/fisiología , SolubilidadRESUMEN
Fetal human cardiac myocytes (FHCM) and a cell line derived from FHCM, termed W1, constitutively express low levels of MHC class I antigens and significant levels of ICAM-1 (CD54), and LFA-3 (CD58) but do not express LFA-1 alpha (CD11a), LFA-1 beta (CD18), GMP-140 (CD62), BB1-B7, VCAM-1, and ELAM-1. In vitro incubation of FHCM or the W-1 cell line for varying periods with varying concentrations of IFN-gamma, TNF-alpha, Poly IC, LPS, IL-alpha, IL-1 beta, PMA, PDBu, and supernatant fluids from Con A-activated PBMC or allogeneic MLR cultures failed to induce cell adhesion molecules (CAMs) or costimulatory molecules that are not constitutively expressed on these cells except for MHC class II antigens. In addition, IFN-gamma, Con A, and MLR supernatant fluids (in order of biological activity) not only induced MHC class II antigens but also markedly increased the mean density of expression per cell of MHC class I and ICAM-1. Analysis of the stability of MHC class I/II molecules using agents like brefeldin-A and Western blot analysis of MHC class II molecules suggest that these ligands are very stably expressed on myocytes. Our previous studies have documented the failure of MHC-expressing FHCM to induce an alloproliferative response. The results of the present studies show that this failure is not secondary to the absence of ICAM-1 or LFA-3 or the presence of unstable MHC molecules but is most likely due to the absence of other CAMs/costimulatory molecules that are critically required for inducing allogeneic activation.
Asunto(s)
Moléculas de Adhesión Celular/análisis , Moléculas de Adhesión Celular/fisiología , Trasplante de Corazón/inmunología , Miocardio/citología , Línea Celular Transformada , Estabilidad de Medicamentos , Endotelio Vascular/química , Endotelio Vascular/citología , Feto/citología , Rechazo de Injerto , Corazón/embriología , Antígenos de Histocompatibilidad Clase II , Humanos , Miocardio/química , Venas Umbilicales/citologíaRESUMEN
The development of post-transplantation coronary graft disease (CGD) is a major cause of late morbidity and mortality. Recent reports have suggested that CGD is a type of chronic vascular rejection, possibly enhanced by cofactors such as concurrent CMV infection and hyperlipidemia. It remains controversial whether established CGD can be improved by modifications in immunosuppressive therapy. The purpose of this study was to examine whether CsA could reverse or halt the progression of CGD after it was already established. Lewis to Fisher (F-344) heterotopic heart allografts develop CGD resembling human disease. Group 1 (n = 29) had no CsA therapy for chronic rat CMV (RCMV) infection in recipients for 8 weeks before transplant. Group 2 (n = 17) had chronic RCMV infection along with CsA therapy from days 15 to 28 post-transplant. Allografts were killed at 2 and 4 weeks and 90 days post-transplantation. In group 1, leukocyte adhesion to arterial endothelium and intimal hyperplasia were well established at 2 weeks and progressed to stenotic, proliferative arterial lesions at 4 weeks. In group 2, CsA therapy was effective in significantly reversing histologic parameters of vascular rejection such as leukocyte adhesion, intimal proliferation, and periarterial edema at 4 weeks. By 90 days, however, arterial pathology was as severe as in group 1. In conclusion, these results support the hypothesis that CGD is a form of chronic vascular rejection, and once established, can be significantly modified by CsA therapy. These effects are not permanent, and progressive CGD recurs after CsA therapy is discontinued.
Asunto(s)
Arteriosclerosis/prevención & control , Ciclosporina/uso terapéutico , Animales , Arteriosclerosis/etiología , Arteriosclerosis/microbiología , Infecciones por Citomegalovirus/complicaciones , Rechazo de Injerto , Trasplante de Corazón/efectos adversos , Ratas , Ratas Endogámicas F344 , Ratas Endogámicas Lew , Factores de Tiempo , Trasplante Homólogo/inmunologíaRESUMEN
Twenty patients with decreased left ventricular (LV) function and endomyocardial biopsy-proved myocarditis (9 patients) or borderline myocarditis (11 patients) were studied to determine whether these 2 histologic subsets of patients with inflammatory heart disease differed in their response to a 6- to 8-week course of immunosuppressive therapy. All patients received a regimen of prednisone, 1.0 mg/kg/day, and azathioprine, 1.5 mg/kg/day, followed by repeat endomyocardial biopsy and reevaluation of LV function. LV function improved significantly in the group with borderline myocarditis, as assessed by LV stroke work--end-diastolic volume ratio (0.26 +/- 0.17 to 0.54 +/- 0.31 kg.m.ml-1, p less than 0.02), heart rate corrected velocity of circumferential shortening (0.49 +/- 0.30 to 0.80 +/- 0.29 circ.s-1, p less than 0.05), and LV ejection fraction (0.30 +/- 0.15 to 0.47 +/- 0.13, p less than 0.05). LV end-diastolic and end-systolic volume indexes also decreased significantly from 129 +/- 40 to 94 +/- 38 (p less than 0.05) and 90 +/- 37 to 49 +/- 26 ml (p less than 0.02), respectively. No significant change in these indexes of LV function or volume occurred in the myocarditis group. Whereas salutory improvements in cardiac output and filling pressures were found in both groups, objective improvement in LV function assessed by complementary indexes of contractility was greatest in the borderline myocarditis group. It is concluded that short-term immunosuppressive therapy improves LV contractile function and appears to be associated with regression of ventricular dilatation in patients with borderline myocarditis to a greater extent than patients with myocarditis.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Azatioprina/uso terapéutico , Terapia de Inmunosupresión , Miocarditis/tratamiento farmacológico , Prednisona/uso terapéutico , Función Ventricular Izquierda/efectos de los fármacos , Adolescente , Adulto , Anciano , Azatioprina/efectos adversos , Ecocardiografía , Femenino , Insuficiencia Cardíaca/etiología , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Contracción Miocárdica/efectos de los fármacos , Miocarditis/complicaciones , Miocarditis/patología , Miocarditis/fisiopatología , Prednisona/efectos adversosRESUMEN
The prevalence and incidence of left ventricular (LV) dysfunction was examined in patients infected with the human immunodeficiency virus (HIV). Sixty-nine randomly selected patients diagnosed with HIV infection who were followed in HIV clinics were prospectively evaluated by 2-dimensional echocardiography. Mean follow-up duration was 11 months. Additionally, 39 consecutive HIV-infected patients referred to the Cardiomyopathy Service and found to have LV dysfunction by 2-dimensional echocardiography were also studied. Of the 39 referred patients, 34 (87%) were referred for recent onset, unexplained, congestive heart failure. During this time, the HIV clinic population comprised 1,819 alive and actively followed patients; the 39 cardiomyopathy referrals therefore constituted a crude rate of 2.1% for this population. Of the 69 prospectively studied patients without clinical heart disease, a 14.5% prevalence of global LV hypokinesia and an incidence of 18%/patient-year were found. During a maximal 18-month follow-up period, 4 prospective patients (5.8%) developed symptoms of congestive heart failure. A greater proportion of prospective and referred patients with LV dysfunction had CD4 counts < 100/mm3 (62 and 79%, respectively) than did that of those without LV dysfunction (35%). In conclusion, the high rate of unexpected LV dysfunction in this HIV-infected population suggests that early cardiac contractile abnormalities may involve a significant number of patients, most of whom have low CD4 counts. A subgroup of these patients appears to progress to symptomatic congestive heart failure.
Asunto(s)
Cardiomiopatía Dilatada/epidemiología , Cardiomiopatía Dilatada/fisiopatología , Infecciones por VIH/complicaciones , Función Ventricular Izquierda , Adulto , Cardiomiopatía Dilatada/diagnóstico por imagen , Ecocardiografía , Femenino , Infecciones por VIH/fisiopatología , Humanos , Incidencia , Masculino , Prevalencia , Estudios ProspectivosRESUMEN
From January 1985 through December 1990, 534 patients underwent endomyocardial biopsy at Johns Hopkins Hospital for suspected myocarditis. One hundred thirty-eight (26%) biopsy specimens were diagnosed histologically by 2 cardiac pathologists as either active (n = 85, 16%) or borderline (n = 53, 10%) myocarditis. Of the 138 patients, 60 were excluded based on either specific concurrent clinical conditions or noncongestive heart failure presentations. Immunohistochemical staining for common leukocyte antigen infiltrating cells performed on the remaining 78 specimens confirmed the presence of focal or multifocal inflammatory infiltrates in 58, of which 49 had histologic evidence of active myocarditis. All 49 patients presented with congestive heart failure and left ventricular ejection fractions of < 40%. Compared with patients with either idiopathic dilated cardiomyopathy (n = 207) or ischemic cardiomyopathy (n = 44), these patients with myocarditis had a less striking male predominance (58 vs 69 and 83%, respectively) (p = 0.02) and were younger (43 +/- 16 vs 50 +/- 17 and 55 +/- 13 years, respectively, p = 0.005). Racial distributions were similar. A recent history of a discrete flu-like illness was obtained in 52%, two-thirds of which were clustered between the months of December and March. Onset of heart failure peaked between December and April (63% and was low between May through September (22%). A peak in the proportion of patients found to have active myocarditis on biopsy occurred in 1986 (17 vs 7 to 10% in other years).(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Endocardio/patología , Insuficiencia Cardíaca/patología , Miocarditis/patología , Adulto , Biopsia , Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/patología , Estudios de Cohortes , Femenino , Insuficiencia Cardíaca/etiología , Humanos , Masculino , Persona de Mediana Edad , Miocarditis/epidemiología , Miocarditis/etiología , Prevalencia , Estaciones del Año , Factores SexualesRESUMEN
Human cardiac myocytes do not express detectable levels of major histocompatibility complex (MHC) class II antigens and express low levels, if any, of MHC class I antigens. During rejection episodes, cardiac biopsies show massive increases of MHC antigens, which are thought to be induced by cytokines released by donor-sensitized recipient mononuclear cells. In efforts to determine the nature of the cytokines that induce MHC expression on cardiac myocytes, human fetal cardiac myocyte cultures were established. Interferon-alpha (IFN-alpha), interferon-gamma (IFN-gamma), interleukin (IL)-1, IL-2, IL-3, IL-4, and tumor necrosis factor (TNF)-alpha were added to these cultures and dose/kinetics of MHC class I/II induction quantitated. Data show that IFN-gamma induces both MHC class I and II expression, and all the other cytokines (except IL-2) induce only MHC class I but not class II. Cytokines used in combination showed that IFN-alpha with TNF-alpha was the only combination that induced MHC class II expression. Addition of immunosuppressive drugs such as cytoxan, azathioprine, cyclosporine-A, and FK-506, even when added at the initiation of the cultures, did not appreciably affect the ability of the appropriate cytokines to induce MHC expression by the myocytes in vitro.