Ahvie Herskowitz

A Clinical Trial of Immunosuppressive Therapy for Myocarditis

BACKGROUND Myocarditis is a serious disorder, and treatment options are limited. This trial was designed to determine whether immunosuppressive therapy improves left ventricular function in patients with myocarditis and to examine measures of the immune response as predictors of the severity and outcome of disease. METHODS We randomly assigned 111 patients with a histopathological diagnosis of myocarditis and a left ventricular ejection fraction of less than 0.45 to receive conventional therapy alone or combined with a 24-week regimen of immunosuppressive therapy. Immunosuppressive therapy consisted of prednisone with either cyclosporine or azathioprine. The primary outcome measure was a change in the left ventricular ejection fraction at 28 weeks. RESULTS In the group as a whole, the mean (+/- SE) left ventricular ejection fraction improved from 0.25 +/- 0.01 at base line to 0.34 +/- 0.02 at 28 weeks (P < 0.001). The mean change in the left ventricular ejection fraction at 28 weeks did not differ significantly between the group of patients who received immunosuppressive therapy (a gain of 0.10; 95 percent confidence interval, 0.07 to 0.12) and the control group (a gain of 0.07; 95 percent confidence interval, 0.03 to 0.12). A higher left ventricular ejection fraction at base line, less intensive conventional drug therapy at base line, and a shorter duration of disease, but not the treatment assignment, were positive independent predictors of the left ventricular ejection fraction at week 28. There was no significant difference in survival between the two groups (P = 0.96). The mortality rate for the entire group was 20 percent at 1 year and 56 percent at 4.3 years. Features suggesting an effective inflammatory response were associated with less severe initial disease. CONCLUSIONS Our results do not support routine treatment of myocarditis with immunosuppressive drugs. Ventricular function improved regardless of whether patients received immunosuppressive therapy, but long-term mortality was high. Patients with a vigorous inflammatory response had less severe disease.

Clinicopathoiogic description of myocarditis

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.

Nitric oxide inhibits viral replication in murine myocarditis.

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.

Mycarditis and cardiotropic viral infection associated with severe left ventricular dysfunction in late-stage infection with human immunodeficiency virus☆

Abstract 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 Conclusions. This study demonstrates that cardiotropic virus infection and myocarditis may be important in the pathogenesis of symptomatic HIV-associated cardiomyopathy.

Circulating heart-reactive antibodies in patients with myocarditis or cardiomyopathy

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.

Cardiomyopathy Associated with Antiretroviral Therapy in Patients with HIV Infection: A Report of Six Cases

Excerpt Symptomatic congestive heart failure has been described as part of the spectrum of human immunodeficiency virus (HlV)-related cardiac disease (1-3). Echocardiographic studies have further d...

Prevalence and incidence of left ventricular dysfunction in patients with human immunodeficiency virus infection

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.

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)

Induction of major histocompatibility complex antigens within the myocardium of patients with active myocarditis: A nonhistologic marker of myocarditis

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.

Inhibition of neutrophil adhesion during cardiopulmonary bypass

Blood contact with synthetic surfaces during cardiopulmonary bypass (CPB) causes a diffuse inflammatory reaction that includes neutrophil activation. The purpose of this study was to determine if inhibition of neutrophil adhesion with a new antiinflammatory agent NPC 15669 (N-(9H-(2,7-dimethylfluorenyl-9-methoxy)-carbonyl)-L-leucine) could reduce pulmonary injury in a porcine model of CPB. NPC 15669 blocks adherence of activated neutrophils by inhibiting upregulation of the Mac-1 (CD11b/CD18) adhesion molecule. Sixteen piglets underwent 2 hours of hypothermic CPB followed by 2 hours of observation; 8 received NPC 15669 (10 mg/kg intravenous bolus followed by 6 mg.kg-1.h-1 intravenous infusion) and 8 received equal volumes of vehicle. After 90 minutes of CPB, expression of neutrophil adhesion molecule subunit CD18 increased 118% in control piglets but only 36% in piglets treated with NPC 15669 (p < 0.01). Although neutropenia developed in all animals during CPB, lung tissue myeloperoxidase content was significantly lower in treated than in control animals 2 hours after CPB (94.9 +/- 10.4 versus 46.9 +/- 5.5 mumol.10 mg-1.min-1; p < 0.002). Free radical-mediated lipid peroxidation (quantitated by spectrophotometric assay of plasma conjugated dienes) was significantly reduced by treatment with NPC 15669 during and after CPB. Pulmonary function was better in NPC 15669-treated animals: 2 hours after CPB, pulmonary vascular resistance increased 477% in control piglets but only 140% in piglets receiving NPC 15669 (p < 0.03); arterial oxygen tension was significantly greater in piglets receiving NPC 15669 (428 +/- 33 mm Hg) than in controls (141 +/- 46; p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)