Intravenous immunoglobulin — Indications and mechanisms in cardiovascular diseases

doi:10.1016/j.autrev.2008.04.001

Autoimmunity Reviews

Volume 7, Issue 6, June 2008, Pages 445-452

https://doi.org/10.1016/j.autrev.2008.04.001 Get rights and content

Abstract

Intravenous immunoglobulin (IVIG) is efficient in various immune mediated conditions. Various cardiovascular diseases are mediated by inflammatory processes and autoimmune mechanisms. Therefore, it seems conceivable to employ IVIG as an immunomodulating therapy in such indications. In this paper we review the possible anti-inflammatory effects of IVIG transfusion, and discuss the possible clinical implications in cardiology. Besides the established use of IVIG in Kawasaki disease, IVIG may be beneficial in some cases of heart failure, dilated cardiomyopathy, myocarditis, pericardial diseases, neonatal lupus, in the prevention of cardiac rejection following transplantation, and in modulating atherosclerosis. IVIG has been proven to be ineffective in rheumatic fever. Although uncommon, complications may arise including myocardial infarction, renal failure and hyperviscosity. IVIG should be administered based on accepted modes of transfusion.

Section snippets

Congestive heart failure (CHF)

Severe CHF is associated with a proinflammatory state due to an increase of serum tumor necrosis factor alpha (TNFα), interleukin-1, interleukin-18 and interleukin-6, Toll-like receptor 4, complement activation, and decreased levels of interleukin-10 [2]. Proinflammatory cytokines have been excessively secreted by lymphocytes and monocytes in the coronary circulation, and in the failing myocardium [2]. Other studies investigating patients with mild to moderate heart failure compared with

IVIG in CHF

IVIG has anti-inflammatory properties and induces a change of circulating cytokines. Therefore it was considered as a treatment for CHF patients [5]. Prolonged treatment of patients with CHF classified as functional class NYHA II/III using IVIG, induced an anti-inflammatory effect, with an associated significant increase of left ventricular ejection fraction regardless of the cause of the CHF [5]. However, IVIG had no beneficial effect in patients with long standing heart disease and very low

Dilated cardiomyopathy (DCM)

DCM is defined as a myocardial dilatation and dysfunction, which may be caused by various triggers such as viral infections, toxins, chemotherapeutic agents, neuromuscular diseases, metabolic abnormalities, inflammatory conditions and nutritional deficiencies. A distinct group of DCM cases that cannot be explained by either causes is defined as idiopathic. Although the pathogenesis is still unclear, several predisposing conditions may coexist, along with immune abnormalities and autoantibodies

Peripartum cardiomyopathy (PPCM)

PPCM is a rare and distinct clinical entity of an obscure nature, although it is believed that autoimmune mechanisms take part in the pathogenesis. In 30%–50% of the patients, a significant improvement of the cardiac function occurred spontaneously after 6 months, but otherwise the prognosis is poor [14]. IVIG treatment in patients with PPCM had increased the ejection fraction of the patients by 26 ± 8 EF units, compared with 13 ± 13 EF units in the untreated group [14]. Despite the promising

Myocarditis

Acute myocarditis is defined as an inflammatory process with a myocardial involvement, usually following a flu-like illness. Heart failure may be subclinical or manifest as a fulminant due to cardiac dysfunction [15]. Treatment using corticosteroids or cytotoxic agents has proven to be ineffective [16].

Several mechanisms were suggested in order to explain cardiac injury in myocarditis. Viral infections are the leading cause of myocarditis, although cardiac injury may arise from immunologic

Pericardial diseases

Acute pericarditis is complicated by chronic idiopathic pericarditis (CIP) in 25% of cases. It is presumed to be somewhat associated with viral infections and autoantibodies [23]. A report of 4 cases of unresponsive CIP that were treated with IVIG resulted in a remarkable response in 3 patients with a longstanding remission with no need for further steroid treatment [23]. Several other case reports were consistent with these findings [24]. Therefore IVIG may serve as an alternative therapy for

Atherosclerosis

Atherosclerosis is believed to be mediated also by inflammatory process, a notion that is supported by findings of macrophage and lymphocytes in the atherosclerotic plaque [27]. Both humoral and cellular arms of the immune system are involved in atherogenesis [28]. Treating laboratory mice with cyclosporine has caused accelerated atherosclerosis, while CD4 and CD8 depleted mice had decreased atherosclerosis. Similarly, T-cell transfusion to immunodeficient mice has caused an increase in

Kawasaki disease

Kawasaki disease, also known as mucocutaneous-lymph node syndrome, is a systemic inflammation of small to medium size vessels of unknown etiology. Kawasaki is a well known FDA approved absolute indication for IVIG therapy, which results in a significant decrease in coronary artery aneurysms when given within 10 days following the onset of fever.

Rheumatic fever

Due to a lack of therapeutic options for an established RF, several agents have been proposed in the attempt to change the natural history and cardiac manifestations. Several case reports had promising results in attempting IVIG treatment for rheumatic carditis. However, a randomized placebo-controlled trial in 59 patients with RF who were treated with either IVIG or placebo revealed that IVIG treatment did not reduce the valvulitis or altered the natural history of the disease [33]. Therefore

Cardiac transplantation

The presence of high panel reactive antibodies, against HLA 1 (especially in face of over 10% reactivity) increases the risk of early graft rejection, and mortality which may be avoided by selecting a crossed-matched donor [35]. IVIG decreases sensitization and enables transplantation in patients awaiting renal transplantation [36]. Left ventricular assistant device, may serve as a bridge for cardiac transplantation, but also causes patient sensitization by B-cell activation due to the need for

Mechanism of action

A wide variety of immunoglobulins are present in the IVIG preparation. Therefore extended spectrum of activities may arise including immunomodulation, anti-inflammatory and anti-infectious properties. Inflammatory processes and autoimmune mechanisms may serve as mediators in various cardiovascular diseases. It seems only reasonable that immunomodulating therapy would be beneficial in cardiology. Change in circulating cytokines in various cardiac diseases such as heart failure, DCM and

Conclusions

IVIG is considered a mainstream treatment in Kawasaki disease. There is supporting evidence for IVIG efficacy in heart failure, dilated cardiomyopathy, myocarditis, pericardial diseases, neonatal lupus, atherosclerosis, and in the prevention of cardiac rejection following transplantation. IVIG has proven to be ineffective in rheumatic fever. Although uncommon, IVIG treatment may be complicated by myocardial infarction, renal failure and hyperviscosity. In order to avoid complications, protocols

Take-home Messages

•
IVIG preparation is known to have immunomodulating, anti-inflammatory and anti-infectious properties.
•
The pathogenesis of various cardiovascular diseases may be mediated by inflammatory processes and autoimmune mechanisms.
•
Kawasaki is a FDA approved indication for IVIG therapy, which results in a significant decrease in long term complications.
•
There are supporting evidences for the beneficial effect of IVIG in heart failure, dilated cardiomyopathy, myocarditis, pericardial diseases, neonatal

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Intravenous immunoglobulin (IVIG) is used to treat several autoimmune and inflammatory diseases, but some patients are refractory to IVIG and require alternative treatments. Identifying a biomarker that could segregate IVIG responders from non-responders has been a subject of intense research. Unfortunately, previous transcriptomic studies aimed at addressing IVIG resistance have failed to predict a biomarker that could identify IVIG-non-responders. Therefore, we used a novel data mining technique on the publicly available transcriptomic data of Kawasaki disease (KD) patients treated with IVIG to identify potential biomarkers of IVIG response. By studying the boolean patterns hidden in the expression profiles of KD patients undergoing IVIG therapy, we have identified new metabolic pathways implicated in IVIG resistance in KD. These pathways could be used as biomarkers to segregate IVIG non-responders from responders prior to IVIG infusion. Also, boolean analysis of the transcriptomic data could be further extended to identify a universal biomarker that might predict IVIG response in other autoimmune diseases.
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Virus-negative or autoimmune myocarditis(VNM) is an inflammatory disease affecting the myocardium that may occur as a distinct disease with exclusive cardiac involvement, or in the context of systemic autoimmune or inflammatory disorders. The pathogenesis of VNM involves both innate and acquired immunity and is not completely elucidated: an early immune-mediated pathogenic process lead to subacute and chronic stages and eventually results in tissue remodeling, fibrosis, contractile dysfunction, dilated cardiomyopathy and arrhythmic burden, accounting for a dismal prognosis. Treatment interventions effectively curbing the acute inflammatory process at an early stage can prevent late cardiac remodeling and improve patient's outcome. The mainstay of treatment of VNM remains symptomatic therapy of heart failure and arrhythmia, while the use of immunosuppressive treatments has long been considered controversial until recently, and strategies effectively targeting the inflammatory and immune-mediated substrate of the disease remain elusive. Only steroids and azathioprine have been tested in clinical trials, and nowadays represent the therapy of choice. A substantial proportion of patients are resistant to first line strategies, suggesting that some critical inflammatory mechanisms are not responsive to conventional immunosuppression with steroids and azathioprine, or experience drug-related adverse events. Thus, second-line targeted therapeutic strategies to treat VNM are eagerly awaited.
Recent data on the pathogenic mechanisms underlying myocardial inflammation are paving the way to novel, promising treatment strategies for myocarditis, which could reformulate future treatment strategies for VNM.
In this review, we summarize the current therapeutic opportunities, beyond corticosteroids, to treat VNM, including conventional and biologic immunosuppressive drugs and cytokine blocking agents.
Efficacy and safety of mycophenolate mofetil in patients with virus-negative lymphocytic myocarditis: A prospective cohort study
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Citation Excerpt :
To date, only few observational studies and case reports supported the efficacy of second-line immunosuppressive agents in the treatment of VNLM, nearly unequivocally associated with systemic CTDs, SSc among others [12–20,37]. Chiefly, case series and case reports recently reported the efficacy of rituximab, methotrexate and intravenous immunoglobulin (IVIG) in patients with myocarditis in the context of CTDs and in patients with acute myocarditis; however, the strength of these data is limited by the small number of patients [12,13,38,39]. In the absence of multi-center randomized studies in biopsy-proven myocarditis/DCM ESC Guidelines do not give recommendations for the use of IVIG [40].
virus-negative lymphocytic myocarditis (VNLM) is a severe inflammatory heart disease with elusive therapies. We aimed to assess the efficacy of mycophenolate-mofetil (MMF) in patients with VNLM.
Methods: patients were enrolled in this prospective cohort study and were treated with MMF, as the initial treatment in case of concomitant systemic immune diseases (SIDs), or as rescue therapy in isolated myocarditis intolerant/resistant to azathioprine. All were initially evaluated for endomyocardial biopsy; ECG, 24-h Holter, echocardiography, troponin T and NT-proBNP were obtained in all patients at baseline and after 6 months. The primary end-point was the change in left-ventricular ejection-fraction (LVEF) on echocardiogram after 6 months. Secondary outcomes: decrease in serum NT-proBNP and troponin-T levels, reduction of LV end-diastolic-volume (LVEDV), amelioration of regional wall motion abnormalities (RWMA), and modification of clinical status.
20 patients (10 females, median age at diagnosis 32 [41–59] years) were enrolled. Baseline echocardiography revealed a reduced LVEF (<55%) in 11 patients (55%) and a median LV-EF of 53.5 [44–60.5]%. Baseline median troponin T and NT-proBNP were 50.5 (14.4–288.5)ng/L and 257.0 (90.5–912.0)pg/ml, respectively. After 6 months, the median LVEF significantly improved (57 [50–61]%,p = 0.016), irrespective of concomitant steroid dose. Consistently, after 6 months LVEDV decreased from 135 ± 50 ml to 114 ± 38 ml (p < 0.001), and only 6 patients had RWMA, compared to 14 at baseline (p = 0.016). The amelioration of cardiac function was paralleled by a reduction of median troponin T (12.0 [10.0–24.0],p = 0.02) and NT-proBNP(79.5 [74.5-223-2],p = 0.007) and by a reduction in the number of patients with dyspnea NYHA class II-III(p = 0.02). None of the patients required drug discontinuation.
MMF migh be a safe and effective therapeutic option in VNLM, both as first-line agent and as a rescue therapy.
Neonatal dilated cardiomyopathy
2017, Revista Portuguesa de Cardiologia
Cardiomyopathies are rare diseases of the heart muscle, of multiple causes, that manifest with various structural and functional phenotypes but are invariably associated with cardiac dysfunction. Dilated cardiomyopathy is the commonest cardiomyopathy in children, and the majority present before one year of age. Its etiology may be acquired or genetic. Myocarditis is an important cause and is responsible for the majority of acquired cases. Inherited (familial) forms of dilated cardiomyopathy may occur in 25-50% of patients. Echocardiographic and tissue Doppler studies are the basis for diagnosis of dilated cardiomyopathy in most patients. Marked dilatation of the left ventricle with global hypokinesis is the hallmark of the disease. This review will cover the classification, epidemiology and management of newborns with dilated cardiomyopathy. In particular, a comprehensive and up-to-date review of the genetic study of dilated cardiomyopathy and of detailed echocardiographic assessment of these patients will be presented.
As cardiomiopatias são doenças raras do músculo cardíaco, de múltiplas causas, que se manifestam com vários fenótipos estruturais e funcionais, mas invariavelmente associadas a disfunção cardíaca. A cardiomiopatia dilatada é a forma mais comum em crianças, apresentando-se maioritariamente antes do ano de idade. A sua etiologia pode ser adquirida ou genética. A miocardite é uma importante causa, responsável pela maioria dos casos adquiridos. As formas hereditárias (familiares) de cardiomiopatia dilatada podem ocorrer em 25-50% dos pacientes. Os estudos ecocardiográficos e Doppler são a base para o seu diagnóstico, caracterizando-se por uma acentuada dilatação do ventrículo esquerdo com hipocinesia global. Neste artigo serão abordadas a classificação, a epidemiologia e a abordagem dos recém-nascidos com cardiomiopatia dilatada. Em particular, será apresentada uma revisão abrangente e atualizada da avaliação genética desta entidade, bem como aspetos detalhados da ecocardiografia nestes pacientes.
Cardiomyopathy — An approach to the autoimmune background
2017, Autoimmunity Reviews
Autoimmunity is increasingly accepted as the origin or amplifier of various diseases. In contrast to classic autoantibodies (AABs), which induce immune responses resulting in the destruction of the affected tissue, an additional class of AABs is directed against G-protein-coupled receptors (GPCRs; GPCR-AABs). GPCR-AABs functionally affect their related GPCRs for activation of receptor mediated signal cascades. Diseases which are characterized by the presence of GPCR-AABs with evidence for disease-specific pathogenic activity could be named “functional autoantibody disease”.
We briefly summarize here the historical view on autoimmunity in cardiomyopathy, followed by an approach to the mechanistic autoimmunity background. Furthermore, autoantibodies with outstanding importance for cardiomyopathies as a functional autoantibody disease, such as GPCR-AABs, and mainly those directed against the beta1-adrenergic and muscarinic 2 receptor autoantibodies, are introduced. Anti-cardiac myosin and anti-cardiac troponin autoantibodies, as further potential players in autoimmune cardiomyopathy, are additionally taken into account. The basic view on the autoantibodies, their related receptor interactions and pathogenic consequences are presented.
Focused specifically on GPCR-AABs, “pros and cons” of assays such as indirect assays (functional changes of cell preparations are monitored after GPCR-AAB receptor binding) and direct assays based on the ELISA technologies (GPCR epitope mimics for GPCR-AAB binding) are critically discussed.
Last but not least, treatment strategies for “functional autoantibody disease”, such as for GPCR-AAB removal (therapeutic plasma exchange, immunoadsorption) and in vivo GPCR-AAB attack such as intravenous IgG treatment (IVIG), B-cell depletion and GPCR-AAB binding and neutralization, are critically reflected with respect to their patient benefits.

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Intravenous immunoglobulin — Indications and mechanisms in cardiovascular diseases

Abstract

Section snippets

Congestive heart failure (CHF)

IVIG in CHF

Dilated cardiomyopathy (DCM)

Peripartum cardiomyopathy (PPCM)

Myocarditis

Pericardial diseases

Atherosclerosis

Kawasaki disease

Rheumatic fever

Cardiac transplantation

Mechanism of action

Conclusions

Take-home Messages

Autoimmun Rev

Am J Cardiol

Int J Cardiol

Autoimmun Rev

Am Heart J

J Am Coll Cardiol

Am J Med Sci

Int J Cardiol

Int J Cardiol

Heart Lung

Autoimmun Rev

J Thorac Cardiovasc Surg

Autoimmun Rev

i.v.IG for autoimmune, fibrosis, and malignant conditions: our experience with 200 patients

J Clin Immunol

Immunomodulating therapy with intravenous immunoglobulin in patients with chronic heart failure

Circulation

Review of trials in chronic heart failure showing broad-spectrum anti-inflammatory approaches

Am J Cardiol

Pathophysiological role of cytokines in congestive heart failure

Annu Rev Med

Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy

Circulation

Beneficial effect on cardiac function by intravenous immunoglobulin treatment in patients with dilated cardiomyopathy is not due to neutralization of anti-receptor autoantibody

Autoimmunity