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A Herskowitz

Publications and source records attributed to A Herskowitz.

At least 55 records · Page 3Linked to original sources
PubMed1993

Autoimmunity in myocarditis: models and mechanisms.

The International Symposium on Immunologically Mediated Heart Disease highlighted a number of controversial issues about the etiology and pathogenesis of myocarditis and dilated cardiomyopathy. They include the role of virus infection in initiating the disease, genetic regulation in the host, the interplay between virus persistence and autoimmunity in producing the later phases of disease, the antigenic determinants responsible for inducing autoimmune disease, and the pathogenetic effector mechanisms. Most of these questions can best be explored by detailed analysis of animal models followed by careful correlation with clinical, epidemiological, and pathological studies of human cases of myocarditis and dilated cardiomyopathy. Based on the new insights gained from these studies, future therapies for immunologically mediated heart disease may emerge.

Antibodies, Anti-Idiotypic↗
PubMed1993

Viral myocarditis leading to cardiomyopathy: do cytokines contribute to pathogenesis?

Cardiotropic virus infection of mice typically produces florid myocardial inflammation and, in certain strains, elicits a chronic postinfectious autoimmune myocarditis. In humans, myocarditis may progress into cardiomyopathy manifested by interstitial fibrosis and myocyte hypertrophy in the absence of myocardial inflammation. Because of their pleiotropic effects, cytokines may provide a common link between connective tissue changes, myocardial injury, and cardiac autoimmunity. To explore such possibilities, histopathological and serological studies were performed on virus-infected mice which were or were not subject to cytokine manipulation. Mice infected with low doses of encephalomyocarditis virus exhibited little myocardial inflammation although myocyte hypertrophy and reactive fibrosis were common. Profound ultrastructural changes in the interstitium were observed through much of the noninflamed myocardium. B10.A mice which are resistant to the development of postinfectious autoimmune myocarditis developed severe autoimmune myocarditis when infected with Coxsackie virus B3 (CB3) and treated with bacterial lipopolysaccharide (LPS), tumor necrosis factor (TNF), or interleukin 1 (IL-1). B10.A mice given CB3, LPS, TNF, or IL-1 alone did not develop myocarditis and there was no evidence of autoimmune recognition of the heart. When CB3-infected A/J mice, which typically develop autoimmune sequelae to the infection, were treated with an IL-1 receptor antagonist, myocardial injury was diminished and heart antibody activity was reduced. These results suggest that TNF, IL-1, and possibly other cytokines contribute to myocardial pathogenesis and the induction of heart-specific autoimmunity. Further studies may lead to the development of cytokine-based therapeutic approaches to treating myocarditis and cardiomyopathy.

Animals↗
PubMed1993

Complement inhibition with soluble complement receptor type 1 in cardiopulmonary bypass.

Although complement activation during cardiopulmonary bypass (CPB) is well documented, its pathogenic role in postperfusion organ injury is unproven. In this study, soluble human complement receptor type 1 (sCR1), a potent inhibitor of complement activation, was used to determine the contribution of complement activation to pulmonary injury in a porcine model of CPB. In vitro experiments demonstrated that sCR1 inhibits both classic and alternative complement pathways in the pig. Seven control piglets and 6 piglets treated with sCR1 (12 mg/kg intravenously) underwent 2 hours of hypothermic (28 degrees C) CPB followed by 2 hours of observation. In control piglets, total hemolytic complement activity and functional activities of C3 and C5 declined to 61.3%, 67.8%, and 61.4% of prebypass values, respectively, after 2 hours of CPB. Plasma from animals treated with sCR1 had virtually no hemolytic activity (total hemolytic complement activity < 5% of baseline), demonstrating effective complement inhibition. Similar degrees of neutropenia developed in the two groups during CPB, and there was no difference in post-CPB lung tissue myeloperoxidase level. Two hours after CPB, pulmonary vascular resistance increased 338% in control piglets but only 147% in piglets pretreated with sCR1 (p < 0.05); the alveolar-arterial gradient was not significantly different between controls (331 +/- 52 mm Hg) and piglets receiving sCR1 (290 +/- 85 mm Hg). Histologic examination revealed similar degrees of pulmonary edema in both groups. These data constitute direct evidence that complement activation plays a pathogenic role in lung injury after CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Heparin-coated bypass circuits reduce pulmonary injury.

Heparin coating of the extracorporeal circuit not only reduces heparin requirements during cardiac operations but also may reduce organ injury associated with cardiopulmonary bypass (CPB). To examine this possibility, pulmonary injury and neutrophil adhesion molecule expression after CPB were studied in pigs undergoing CPB with a standard extracorporeal circuit (group S, n = 6) or a heparin-coated CPB circuit (Carmeda BioActive Surface) (group HC, n = 6). Pigs received heparin sodium (300 U/kg intravenously) and then underwent 90 minutes of hypothermic (28 degrees C) CPB using membrane oxygenators, followed by 2 hours of observation. Blood samples were obtained for determination of neutrophil number and expression of the neutrophil adhesion molecule subunit CD18 (by immunofluorescence flow cytometry). The CPB-associated injury was less in group HC. Two hours after CPB, the arterial oxygen tension group was higher in group HC (597.2 +/- 31.2 versus 220.5 +/- 42.3 mm Hg; p < 0.0001), the pulmonary vascular resistance was lower in these animals (408.6 +/- 69.4 versus 1,159.8 +/- 202.4 dyne.s.cm-5; p = 0.02), and the static compliance was higher in group HC (66.4 +/- 5.4 versus 39.8 +/- 5.8 mL/mm Hg; p = 0.004). After 60 minutes of CPB, both groups had similar increases in expression of the neutrophil adhesion molecule subunit CD18 (29.4% +/- 19.5% versus 26.0% +/- 24.4%, group S and group HC, respectively) and similar decreases in neutrophil counts (6,056 +/- 1,285 to 2,453 +/- 979 cells/microL versus 6,010 +/- 1,748 to 3,197 +/- 1,225 cells/microL, group S and group HC, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Host T-cell primary allosensitization to MHC class-I- and class-II-expressing human cardiac myocytes requires the presence of a second signal.

Normal FHCMs, or transformed cell lines derived from FHCMs, such as W1, even after induction of MHC antigens by pretreatment with IFN-gamma, failed to induce proliferation of allogeneic human PBMCs in vitro. To test the hypothesis that antigen-specific T-cell activation and proliferation require not only the binding of the TCR with its ligand, the MHC molecule, but also a second signal that involves the interaction of T-cell surface molecules with their natural ligands on the stimulating cells, a mAb against CD28 was used. Cocultures of allogeneic PBMCs with IFN-gamma-pretreated irradiated FHCMs or the W1 cell line in microtiter plates containing immobilized anti-CD28 mAb induced marked stimulator cells MHC class-II-specific proliferative responses. The W1 cell line and FHCMs failed to express detectable levels of the BB1/B7 molecule (the natural ligand for CD28) as determined by flow microfluorometry or mRNA levels coding for BB1/B7 as determined by RT-PCR. These data suggest that one of the probably reasons for the failure of MHC-expressing cardiac myocytes to induce allogeneic activation is the absence of costimulatory signals.

Base Sequence↗
PubMed1993

Late cyclosporine treatment ameliorates established coronary graft disease in rat allografts.

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.

Animals↗
PubMed1993

Tricarboxylic acid cycle activity in postischemic rat hearts.

BACKGROUND: Although myocardial oxidative tricarboxylic acid (TCA) cycle activity and contractile function are closely linked in normal cardiac muscle, their relation during postischemic reperfusion, when contractility often is reduced, is not well defined. METHODS AND RESULTS: To test the hypothesis that oxidative TCA cycle flux is reduced in reperfused myocardium with persistent contractile dysfunction, TCA cycle flux was measured by analyzing the time course of sequential myocardial glutamate labeling during 13C-labeled substrate infusion with 13C nuclear magnetic resonance spectroscopy in beating isolated rat hearts at 37 degrees C. Total TCA cycle flux, indexed by both empirical and mathematical modeling analyses of the 13C data, was not reduced but rather increased in hearts reperfused after 17-20 minutes of ischemia (left ventricular pressure, 73 +/- 5% of preischemic values) compared with flux in developed pressure-matched controls (e.g., total flux, 2.5 +/- 0.4 versus 1.6 +/- 0.1 mumol.min-1.g wet wt-1, respectively; p < 0.01). No TCA cycle activity was detectable by 13C nuclear magnetic resonance in hearts reperfused after 40-45 minutes of ischemia, which lacked contractile recovery and had ultrastructural evidence of irreversible injury. CONCLUSIONS: These results suggest that TCA cycle activity is not persistently decreased in dysfunctional reperfused myocardium after a brief ischemic episode and therefore cannot account for the reduced contractile function at that time.

Animals↗
PubMed1993

Soluble complement receptor type 1 inhibits the complement pathway and prevents contractile failure in the postischemic heart. Evidence that complement activation is required for neutrophil-mediated reperfusion injury.

BACKGROUND: Complement-mediated neutrophil activation has been hypothesized to be an important mechanism of reperfusion injury. It has been proposed that soluble complement receptor 1 (sCR1), a potent inhibitor of both classical and alternative complement pathways, may prevent the complement-dependent activation of polymorphonuclear leukocytes (PMNs) that occurs within postischemic myocardium and thereby inhibit PMN-derived free radical generation and prevent postischemic contractile failure. Therefore, we performed studies to determine the effects of sCR1 on contractile function, PMN adhesion, complement deposition, and PMN-derived free radical generation in the postischemic heart. METHODS AND RESULTS: Studies were performed in an isolated rat heart model in which the isolated effects of given cellular or humoral factors could be determined. Plasma and PMNs were present to study the effects of sCR1 on contractile function, coronary flow, leukocyte adhesion, complement deposition, and PMN-derived free radical generation. Isolated rat hearts were perfused by the method of Langendorff (n = 10 in each group) and subjected to 20 minutes of global ischemia and reperfusion with PMNs and plasma in the presence or absence of sCR1. Left ventricular developed pressure (LVDP), coronary flow (CF), left ventricular end-diastolic pressure (LVEDP), and rate-pressure product (RPP) were measured during the preischemic period, during 1-minute control infusion of PMNs and plasma, and on reflow following 20 minutes of global ischemia. During the preischemic control infusion, no significant alterations in the physiologic parameters were observed, and there was no measurable free radical generation. Reperfusion with sCR1 markedly improved the recovery of postischemic contractile function. LVDP after 45 minutes of reperfusion was 76 +/- 9.8% compared with 32 +/- 6.2% (P < .001). In addition, significant improvements in LVEDP, RPP, and CF were observed in hearts treated with sCR1. Additional experiments were also performed to determine the effect of sCR1 on complement-mediated PMN activation. Measurements of PMN-derived free radical generation were performed in both isolated PMNs and the coronary effluent of hearts using electron paramagnetic resonance spectroscopy (EPR) with the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO). EPR measurements in both isolated PMNs and coronary effluent demonstrated that sCR1 blocked complement-mediated free radical generation from the PMNs. Increased accumulation of PMNs was observed both in hearts treated with sCR1 and in those not treated with sCR1. Immunohistochemical staining of the postischemic myocardial tissue demonstrated marked complement deposition on the endothelial surface of small arterioles and capillaries, which was prevented by sCR1 treatment. Thus, sCR1 did not prevent PMN adhesion but did prevent complement deposition with activation of the PMN oxidative burst. CONCLUSIONS: The potent complement inhibitor sCR1 was found to be effective at preventing postischemic myocardial contractile dysfunction and enhancing the recovery of coronary flow. This study demonstrated that complement activation occurs in postischemic myocardium and is necessary for activation of the neutrophil oxidative burst with the generation of reactive oxygen free radicals. The process of neutrophil adhesion, however, was not affected by sCR1 and was independent of complement factors. These findings demonstrate the sCR1 is a highly potent agent at preventing complement-mediated PMN activation and secondary free radical generation in the postischemic heart. This genetically engineered protein appears to be a promising therapeutic agent in the prevention of myocardial reperfusion injury.

Animals↗
PubMed1993

Back injuries in basketball players.

The basketball player with lower back or lower extremity radicular pain needs to be carefully evaluated. A complete history of any previous symptomatology and a specific history of the new injury are absolutely essential. A careful physical examination with an understanding of the anatomy as well as possible causes of the lower back pain is crucial. An accurate diagnosis is essential in treating every athlete. Most basketball-related lower back injuries will respond to conservative nonsurgical treatment. Rehabilitation is a cornerstone in not only treating the initial symptoms, but decreasing the risks of reinjury. The goal of returning the basketball player to previous performance level as quickly as possible, with a minimal risk of re-injury, is the goal of the team physicians.

Back Injuries↗
PubMed1992

In vivo deposition of myosin-specific autoantibodies in the hearts of mice with experimental autoimmune myocarditis.

Experimental autoimmune myocarditis (EAM) is elicited in certain strains of mice by immunizing with mouse cardiac myosin. Concomitant with the onset of myocardial inflammation is the induction of circulating IgG antibodies to myosin. To further examine the role of myosin in disease, both EAM-susceptible (A/J) and EAM-resistant (B10.A) mice were immunized with myosin emulsified in CFA and examined for myocardial inflammation and IgG deposition. Myocarditis was common in susceptible, but not resistant strain mice. IgG deposition was extensive in A/J mice, but modest in B10.A mice, when compared to controls given adjuvant alone. Localization was independent of inflammatory or necrotic lesions. A spot ELISA indicated that antimyosin IgG antibody-secreting cells were present in the myocardial infiltrate and likely contributed to antibody localization. Antibody was eluted from the hearts of immunized animals and found to react strongly with normal heart tissue by indirect immunohistochemistry. This reactivity was not completely absorbed by skeletal muscle, indicating that some of the antibody was heart-specific. Western immunostaining demonstrated that eluates from immunized A/J and B10.A mice possessed anti-myosin antibody activity; similar reactivity was not observed in eluates from control mice of either strain. Comparison of heart reactivity with syngeneic and allogeneic tissue suggests that although myosin immunization elicits homologous antibody in both strains, each may recognize distinct epitopes. These findings strongly suggest that cardiac myosin or a myosin-like determinant is expressed on the surface of normal mouse myocytes.

Animals↗
PubMed1992

Interleukin 1 or tumor necrosis factor can promote Coxsackie B3-induced myocarditis in resistant B10.A mice.

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.

Animals↗
PubMed1992

Incidental myocarditis with intravenous drug abuse: the pathology, immunopathology, and potential implications for human immunodeficiency virus-associated myocarditis.

Human immunodeficiency virus (HIV)-associated myocarditis is well reported. Many of these patients are also intravenous (IV) drug abusers. This study examined sudden death victims from the Office of the Chief Medical Examiner, State of Maryland, for active myocarditis. A group of HIV-negative drug abusers is compared with a group of HIV-negative victims without any known risk factors for the acquired immunodeficiency syndrome. Using modified Dallas criteria combined with an avidin-biotin-labeled immunoperoxidase procedure, the cases were classified as active, borderline, or absent myocarditis. Serologic analysis for circulating antimyocardial antibody was performed along with phenotypic analysis of the infiltrate. Of the 15 IV drug abuse cases examined, none were positive for HIV (enzyme-linked immunosorbent assay and Western blot). With IV drug abuse as the primary risk factor, five cases demonstrated active myocarditis, while five others had borderline myocarditis. Only one of 10 low-risk patients had a lymphocytic infiltrate consistent with borderline myocarditis. Drug abuse-related myocarditis was associated with cardiac pathology resulting in sudden death in only one case. Antimyocardial antibodies were positive in four of the 15 IV drug abuse cases, including patients with active, borderline, and absent myocarditis. The phenotypic expression of the lymphocytic infiltrates was similar to the findings reported for idiopathic and HIV-related myocarditis (Am J Pathol 137:1365-1371, 1990). Toxicology studies did not implicate any particular drug of abuse, but the increased frequency of myocarditis observed may reflect complications of cocaine or the combined effects of opiates and cocaine. Intravenous drug abuse is an independent risk factor for myocarditis and must be taken into consideration in studies of HIV-associated myocarditis.

Adult↗
PubMed1992

In situ detection of human cytomegalovirus immediate-early gene transcripts within cardiac myocytes of patients with HIV-associated cardiomyopathy.

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.

Adult↗