Review
Immunoadsorption therapy in dilated cardiomyopathy Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/13/15 For personal use only.
Expert Rev. Cardiovasc. Ther. 13(2), 145–152 (2014)
Stephan B Felix*1,2, Daniel Beug1 and Marcus Do¨rr1,2 1 Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany 2 DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany *Author for correspondence: [email protected]
Dilated cardiomyopathy is a common myocardial disease characterized by ventricular chamber enlargement and systolic dysfunction that result in heart failure. In addition to genetic predisposition, viral infection and myocardial inflammation play a causal role in the disease process of dilated cardiomyopathy. Experimental and clinical studies suggest that activation of the humoral immune system, with production of circulating cardiac autoantibodies, plays an important functional role in the development and progression of cardiac dysfunction in patients with dilated cardiomyopathy. Small open-controlled studies showed that removal of circulating antibodies by immunoadsorption results in improvement of cardiac function and decrease in myocardial inflammation. At present, immunoadsorption is an experimental treatment option for improvement of cardiac function – therapy that calls for confirmation by a placebo-controlled multicenter study. KEYWORDS: cardiac antibodies . dilated cardiomyopathy . humoral immune system . immunoadsorption .
immunomodulation
.
myocardial inflammation
From myocarditis to dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction that result in progressive heart failure [1]. DCM is the third most common cause of heart failure and the most frequent disease requiring heart transplantation [1]. It is a clinical diagnosis with a diverse etiology that may include idiopathic, familial genetic, viral, and/or immune, as well as alcoholic/toxic causes. It may also be associated with recognized cardiovascular disease in which the degree of myocardial dysfunction is not explained by abnormal loading conditions or the extent of ischemic damage [2,3]. About 20–35% of DCM cases have been reported as familial [1]. The genetic origin of DCM is heterogeneous, although various gene mutations have been detected, including genes encoding contractile sarcomeric proteins, as well as cytoskeletal/sarcolemmal, nuclear envelope, sarcomere and transcriptional coactivator proteins [1]. In addition to genetic predisposition, viral infection and myocardial inflammation play a causal role in disease initiation and progression of DCM [1]. An association between myocarditis and DCM has been hypothesized for a subset of affected patients [2,4–6]. Biopsyproven myocarditis is accordingly reported in informahealthcare.com
10.1586/14779072.2015.990385
9–16% adult patients with unexplained nonischemic DCM [2,7]. Viral genomes are frequently detected in endomyocardial biopsies (EMBs) of patients with DCM [8]. Both experimental and clinical data indicate that viral infection and inflammatory processes may be involved in the pathogenesis of myocarditis and DCM [2,4–6,9–13]. Viral persistence is associated with progression of cardiac dysfunction [14]. Furthermore, disturbances of the cellular and humoral immune system have been implicated in the development of DCM: abnormalities of the cellular immune system are a common feature of both myocarditis and DCM. For patients with DCM, immunohistological methods have been introduced for diagnosis of myocardial inflammation. Infiltration with lymphocytes and mononuclear cells as well as increased expression of cell adhesion molecules are frequently found phenomena in DCM [15–17]. These findings support the hypothesis that the immune process is still active. In many patients with DCM, the term ‘inflammatory cardiomyopathy’ may therefore be applicable in describing the pathogenesis of the disease process [1]. Therefore, inflammatory cardiomyopathy and DCM are not mutually exclusive [2]. Inflammatory cardiomyopathy is defined by the presence of chronic inflammatory cells in association with left ventricular
2014 Informa UK Ltd
ISSN 1477-9072
145
Review
¨ rr Felix, Beug & Do
Genetic background Pathogen Microbial infection (viruses, bacteria, fungi, etc.)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/13/15 For personal use only.
Phase I
Non-infectious (drugs, toxins, venoms, SLE, sarcoidosis, unknown antigens)
Direct microbial damage
Direct/indirect toxic damage
Exposure of normally hidden antigens to the immune system or antigen mimicry Myocyte death, release of chemokines/cytokines activation of the immune system Activation of cross-or autoreactive Acute myocarditis T cells, induction of autoantibodies Phase II
Autoreactive myocarditis • Microbial agents eliminated • Resolution of inflammation
Chronic myocarditis
Healed myocarditis Phase III
• No microbial agents or drugs • Ongoing inflammation
• Microbial agents present • Ongoing inflammation
• Microbial agents present • No autoantibodies • Ongoing inflammation • Ongoing destruction/ remodeling
Chronic microbial myocarditis
• Microbial agents present • Autoantibodies present • Ongoing inflammation • Ongoing destruction/ remodeling
Chronic microbial and immune myocarditis
• No microbial agents • Autoantibodies present • Ongoing inflammation • Ongoing destruction/ remodeling
Chronic autoreactive myocarditis
• Microbial agents present or not • Autoantibodies present or not • No florid inflammation • Ongoing destruction/ remodeling
Dilated cardiomyopathy
Figure 1. Pathogenetic mechanisms involved in myocarditis and progression to dilated cardiomyopathy. Reproduced with permission from Oxford University Press [2].
dilatation and reduced ejection fraction [18]. Histology and/or immunocytochemistry are, therefore, necessary for diagnosis [18]. In a subset of patients, myocarditis is a precursor of DCM [2,6,19]. In patients with suspected myocarditis, immunohistological signs of inflammation in EMBs are a potent risk factor for identifying patients with myocarditis who are likely to deteriorate [20]. In up to 30% of cases, biopsy-proven myocarditis can progress to DCM and is associated with a poor prognosis [2]. Progression from myocarditis to DCM may occur in patients with histologically confirmed persistent (chronic) inflammation that cannot eliminate the infective microbial agents [2]. Genetic susceptibility and autoimmunity triggered by microbial infections are factors implicated in the pathogenesis of DCM [2,21]. Autoreactive myocarditis is a potential mechanism of chronic myocarditis and of DCM as the final stage of the disease process. Virus-induced injury causes a release of intracellular cardiac proteins that, through activation of inflammatory cells, could lead to autoimmune myocarditis [22]. Experimental studies clearly demonstrate that exposure of cardiac antigens to the immune system induces cardiac damage mediated by autoimmune mechanisms: dendritic cells loaded with a heart-specific self-peptide induce CD4+ T-cell-mediated myocarditis in mice. Toll-like receptor stimulation, in concert with 146
CD40 triggering of self-peptide-loaded dendritic cells, was shown to be required for disease induction [21]. FIGURE 1 shows potential pathogenetic mechanisms involved in myocarditis and progression to DCM. The pathophysiological role of cardiac autoantibodies in DCM
Examples of abnormalities of the humoral immune system that have been well documented in patients with DCM include the presence of various circulating autoantibodies. Thus, antibodies against various epitopes such as mitochondrial proteins [23], cardiac myosin [24], cardiac b1-adrenergic receptors [25], muscarinergic receptors [26] and the sarcolemmal Na-K-ATPase [27] have been identified in affected patients. The functional role of these cardiac autoantibodies is under discussion. Antibodies may reflect an inflammatory response to myocyte necrosis, thereby representing an epiphenomenon or, alternatively, may play an active role in the disease process. Interestingly, in patients with chronic myocarditis and cardiomyopathy, the prevalence of antibodies against cardiac myosin is associated with the deterioration of cardiac function [28]. Experimental data indicate that certain cardiac autoantibodies may play a functional role in DCM: antibodies against the Expert Rev. Cardiovasc. Ther. 13(2), (2014)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/13/15 For personal use only.
Immunoadsorption therapy in DCM
ADP/ATP carrier interact with the calcium channel and possess cardiotoxic properties [23]. In the plasma of patients with DCM, negative inotropic antibodies are detectable that decrease the calcium transients of isolated cardiomyocytes [29]. A recent study by Li et al. demonstrated that anti-cardiac myosin antibodies induced by immunization of rats with cardiac myosin target the b-adrenergic receptor on the heart cell surface and induce cAMP-dependent protein kinase A activity in heart cells. Passive transfer of purified antibodies from cardiac myosin-immunized rats results in IgG deposition and apoptosis in the heart, leading to a cardiomyopathic heart disease phenotype in recipients [30]. Immunization of rodents against peptides derived from cardiovascular G-protein receptors induces morphological changes of myocardial tissue resembling DCM [31,32]. A recent study by Jahns et al. investigated the pathogenic significance of autoantibodies that target cardiac b1-adrenoceptors in DCM: rats immunized against the second extracellular loop of cardiac b1-receptors developed progressive left ventricular dilatation and dysfunction [33]. Interestingly, sera transferred from these immunized animals to unsensitized rats induced the similar cardiomyopathic phenotype, thus demonstrating the pathogenic potential of a particular antibody for development of DCM. Further confirmation of the principle that autoantibodies contribute to induction of the disease process and progression of DCM has been provided in a study by Nishimura et al [34]. The authors of this study showed that mice deficient in the programmed cell death-1 immunoinhibitory coreceptor develop autoimmune DCM with the production of high-titer circulating IgG autoantibodies reactive to a 33-kD protein expressed specifically on the surface of cardiomyocytes. Okazaki et al. were recently able to identify this antigen as cardiac troponin I [35]. Interestingly, immunization against cardiac troponin I but not cardiac troponin T induces in mice severe myocardial inflammation followed by fibrosis and heart failure with increased mortality [36]. Several mechanisms are discussed as causal factors that are involved in the autoimmune response and in cardiac damage: cardiac autoimmunity can be induced by exogenous factors and endogenous factors (such as viral infection) that cause primary myocardial damage with exposure of cardiac autoantigens and consecutive autoimmune response that causes secondary myocardial damage [37]. A virus-induced immune response may be also triggered by molecular mimicry with cross-reactivity between epitopes shared by the virus and antigens of the heart [22,37]. In the clinical setting, progression from myocarditis to DCM may occur in patients with myocarditis who have developed pathogenic cardiac autoantibodies directed against myocardial structural, sarcoplasmic or sarcolemmal proteins [2]. Strikingly, detection of organ-specific anti-heart autoantibodies in asymptomatic relatives of both familial and nonfamilial DCM patients was an independent predictor of progression to DCM, left ventricular enlargement and reduced systolic function as assessed by fractional shortening at 5-year follow-up [38]. informahealthcare.com
Review
Treatment options
In general, drug treatment of DCM is identical to that for the management of heart failure, according to guidelines. Until now, no evidence-based specific therapy is available for treatment of DCM. Despite advances in medical treatment of heart failure, the general prognosis for heart failure is still poor [39,40]. In many cases, heart transplantation remains the only therapeutic option when progression of heart failure cannot be inhibited by pharmacotherapy. In this matter, novel treatment options that address the abnormalities of the immune system may be a promising therapeutic alternative or supplement for patients with heart failure owing to DCM. Antiviral therapy
Innate production of interferons is associated with clinical recovery from viral infections. Exogenous interferons may be protective in chronic viral diseases. An uncontrolled, open-label Phase II study has shown that treatment with IFN-b1a induced viral clearance from myocardial tissue as well as improvement of left ventricular function in patients with reduced left ventricular ejection fraction (LVEF) and myocardial persistence of enteroviral and adeno genomes [41]. IFN-b may also improve survival in patients with enterovirus-associated cardiomyopathy [42]. These findings must be confirmed by large randomized Phase III studies. Immunosuppression
Controversial results have been obtained from studies of the effects of immunosuppression in patients with myocarditis and DCM. A clinical trial of immunosuppressive therapy for myocarditis included patients with histopathological diagnosis of myocarditis according to the Dallas criteria [43] and reduced LVEF (
Immunoadsorption therapy in dilated cardiomyopathy Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/13/15 For personal use only.
Expert Rev. Cardiovasc. Ther. 13(2), 145–152 (2014)
Stephan B Felix*1,2, Daniel Beug1 and Marcus Do¨rr1,2 1 Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany 2 DZHK (German Center for Cardiovascular Research), Partner Site Greifswald, Greifswald, Germany *Author for correspondence: [email protected]
Dilated cardiomyopathy is a common myocardial disease characterized by ventricular chamber enlargement and systolic dysfunction that result in heart failure. In addition to genetic predisposition, viral infection and myocardial inflammation play a causal role in the disease process of dilated cardiomyopathy. Experimental and clinical studies suggest that activation of the humoral immune system, with production of circulating cardiac autoantibodies, plays an important functional role in the development and progression of cardiac dysfunction in patients with dilated cardiomyopathy. Small open-controlled studies showed that removal of circulating antibodies by immunoadsorption results in improvement of cardiac function and decrease in myocardial inflammation. At present, immunoadsorption is an experimental treatment option for improvement of cardiac function – therapy that calls for confirmation by a placebo-controlled multicenter study. KEYWORDS: cardiac antibodies . dilated cardiomyopathy . humoral immune system . immunoadsorption .
immunomodulation
.
myocardial inflammation
From myocarditis to dilated cardiomyopathy
Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction that result in progressive heart failure [1]. DCM is the third most common cause of heart failure and the most frequent disease requiring heart transplantation [1]. It is a clinical diagnosis with a diverse etiology that may include idiopathic, familial genetic, viral, and/or immune, as well as alcoholic/toxic causes. It may also be associated with recognized cardiovascular disease in which the degree of myocardial dysfunction is not explained by abnormal loading conditions or the extent of ischemic damage [2,3]. About 20–35% of DCM cases have been reported as familial [1]. The genetic origin of DCM is heterogeneous, although various gene mutations have been detected, including genes encoding contractile sarcomeric proteins, as well as cytoskeletal/sarcolemmal, nuclear envelope, sarcomere and transcriptional coactivator proteins [1]. In addition to genetic predisposition, viral infection and myocardial inflammation play a causal role in disease initiation and progression of DCM [1]. An association between myocarditis and DCM has been hypothesized for a subset of affected patients [2,4–6]. Biopsyproven myocarditis is accordingly reported in informahealthcare.com
10.1586/14779072.2015.990385
9–16% adult patients with unexplained nonischemic DCM [2,7]. Viral genomes are frequently detected in endomyocardial biopsies (EMBs) of patients with DCM [8]. Both experimental and clinical data indicate that viral infection and inflammatory processes may be involved in the pathogenesis of myocarditis and DCM [2,4–6,9–13]. Viral persistence is associated with progression of cardiac dysfunction [14]. Furthermore, disturbances of the cellular and humoral immune system have been implicated in the development of DCM: abnormalities of the cellular immune system are a common feature of both myocarditis and DCM. For patients with DCM, immunohistological methods have been introduced for diagnosis of myocardial inflammation. Infiltration with lymphocytes and mononuclear cells as well as increased expression of cell adhesion molecules are frequently found phenomena in DCM [15–17]. These findings support the hypothesis that the immune process is still active. In many patients with DCM, the term ‘inflammatory cardiomyopathy’ may therefore be applicable in describing the pathogenesis of the disease process [1]. Therefore, inflammatory cardiomyopathy and DCM are not mutually exclusive [2]. Inflammatory cardiomyopathy is defined by the presence of chronic inflammatory cells in association with left ventricular
2014 Informa UK Ltd
ISSN 1477-9072
145
Review
¨ rr Felix, Beug & Do
Genetic background Pathogen Microbial infection (viruses, bacteria, fungi, etc.)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/13/15 For personal use only.
Phase I
Non-infectious (drugs, toxins, venoms, SLE, sarcoidosis, unknown antigens)
Direct microbial damage
Direct/indirect toxic damage
Exposure of normally hidden antigens to the immune system or antigen mimicry Myocyte death, release of chemokines/cytokines activation of the immune system Activation of cross-or autoreactive Acute myocarditis T cells, induction of autoantibodies Phase II
Autoreactive myocarditis • Microbial agents eliminated • Resolution of inflammation
Chronic myocarditis
Healed myocarditis Phase III
• No microbial agents or drugs • Ongoing inflammation
• Microbial agents present • Ongoing inflammation
• Microbial agents present • No autoantibodies • Ongoing inflammation • Ongoing destruction/ remodeling
Chronic microbial myocarditis
• Microbial agents present • Autoantibodies present • Ongoing inflammation • Ongoing destruction/ remodeling
Chronic microbial and immune myocarditis
• No microbial agents • Autoantibodies present • Ongoing inflammation • Ongoing destruction/ remodeling
Chronic autoreactive myocarditis
• Microbial agents present or not • Autoantibodies present or not • No florid inflammation • Ongoing destruction/ remodeling
Dilated cardiomyopathy
Figure 1. Pathogenetic mechanisms involved in myocarditis and progression to dilated cardiomyopathy. Reproduced with permission from Oxford University Press [2].
dilatation and reduced ejection fraction [18]. Histology and/or immunocytochemistry are, therefore, necessary for diagnosis [18]. In a subset of patients, myocarditis is a precursor of DCM [2,6,19]. In patients with suspected myocarditis, immunohistological signs of inflammation in EMBs are a potent risk factor for identifying patients with myocarditis who are likely to deteriorate [20]. In up to 30% of cases, biopsy-proven myocarditis can progress to DCM and is associated with a poor prognosis [2]. Progression from myocarditis to DCM may occur in patients with histologically confirmed persistent (chronic) inflammation that cannot eliminate the infective microbial agents [2]. Genetic susceptibility and autoimmunity triggered by microbial infections are factors implicated in the pathogenesis of DCM [2,21]. Autoreactive myocarditis is a potential mechanism of chronic myocarditis and of DCM as the final stage of the disease process. Virus-induced injury causes a release of intracellular cardiac proteins that, through activation of inflammatory cells, could lead to autoimmune myocarditis [22]. Experimental studies clearly demonstrate that exposure of cardiac antigens to the immune system induces cardiac damage mediated by autoimmune mechanisms: dendritic cells loaded with a heart-specific self-peptide induce CD4+ T-cell-mediated myocarditis in mice. Toll-like receptor stimulation, in concert with 146
CD40 triggering of self-peptide-loaded dendritic cells, was shown to be required for disease induction [21]. FIGURE 1 shows potential pathogenetic mechanisms involved in myocarditis and progression to DCM. The pathophysiological role of cardiac autoantibodies in DCM
Examples of abnormalities of the humoral immune system that have been well documented in patients with DCM include the presence of various circulating autoantibodies. Thus, antibodies against various epitopes such as mitochondrial proteins [23], cardiac myosin [24], cardiac b1-adrenergic receptors [25], muscarinergic receptors [26] and the sarcolemmal Na-K-ATPase [27] have been identified in affected patients. The functional role of these cardiac autoantibodies is under discussion. Antibodies may reflect an inflammatory response to myocyte necrosis, thereby representing an epiphenomenon or, alternatively, may play an active role in the disease process. Interestingly, in patients with chronic myocarditis and cardiomyopathy, the prevalence of antibodies against cardiac myosin is associated with the deterioration of cardiac function [28]. Experimental data indicate that certain cardiac autoantibodies may play a functional role in DCM: antibodies against the Expert Rev. Cardiovasc. Ther. 13(2), (2014)
Expert Review of Cardiovascular Therapy Downloaded from informahealthcare.com by Nyu Medical Center on 02/13/15 For personal use only.
Immunoadsorption therapy in DCM
ADP/ATP carrier interact with the calcium channel and possess cardiotoxic properties [23]. In the plasma of patients with DCM, negative inotropic antibodies are detectable that decrease the calcium transients of isolated cardiomyocytes [29]. A recent study by Li et al. demonstrated that anti-cardiac myosin antibodies induced by immunization of rats with cardiac myosin target the b-adrenergic receptor on the heart cell surface and induce cAMP-dependent protein kinase A activity in heart cells. Passive transfer of purified antibodies from cardiac myosin-immunized rats results in IgG deposition and apoptosis in the heart, leading to a cardiomyopathic heart disease phenotype in recipients [30]. Immunization of rodents against peptides derived from cardiovascular G-protein receptors induces morphological changes of myocardial tissue resembling DCM [31,32]. A recent study by Jahns et al. investigated the pathogenic significance of autoantibodies that target cardiac b1-adrenoceptors in DCM: rats immunized against the second extracellular loop of cardiac b1-receptors developed progressive left ventricular dilatation and dysfunction [33]. Interestingly, sera transferred from these immunized animals to unsensitized rats induced the similar cardiomyopathic phenotype, thus demonstrating the pathogenic potential of a particular antibody for development of DCM. Further confirmation of the principle that autoantibodies contribute to induction of the disease process and progression of DCM has been provided in a study by Nishimura et al [34]. The authors of this study showed that mice deficient in the programmed cell death-1 immunoinhibitory coreceptor develop autoimmune DCM with the production of high-titer circulating IgG autoantibodies reactive to a 33-kD protein expressed specifically on the surface of cardiomyocytes. Okazaki et al. were recently able to identify this antigen as cardiac troponin I [35]. Interestingly, immunization against cardiac troponin I but not cardiac troponin T induces in mice severe myocardial inflammation followed by fibrosis and heart failure with increased mortality [36]. Several mechanisms are discussed as causal factors that are involved in the autoimmune response and in cardiac damage: cardiac autoimmunity can be induced by exogenous factors and endogenous factors (such as viral infection) that cause primary myocardial damage with exposure of cardiac autoantigens and consecutive autoimmune response that causes secondary myocardial damage [37]. A virus-induced immune response may be also triggered by molecular mimicry with cross-reactivity between epitopes shared by the virus and antigens of the heart [22,37]. In the clinical setting, progression from myocarditis to DCM may occur in patients with myocarditis who have developed pathogenic cardiac autoantibodies directed against myocardial structural, sarcoplasmic or sarcolemmal proteins [2]. Strikingly, detection of organ-specific anti-heart autoantibodies in asymptomatic relatives of both familial and nonfamilial DCM patients was an independent predictor of progression to DCM, left ventricular enlargement and reduced systolic function as assessed by fractional shortening at 5-year follow-up [38]. informahealthcare.com
Review
Treatment options
In general, drug treatment of DCM is identical to that for the management of heart failure, according to guidelines. Until now, no evidence-based specific therapy is available for treatment of DCM. Despite advances in medical treatment of heart failure, the general prognosis for heart failure is still poor [39,40]. In many cases, heart transplantation remains the only therapeutic option when progression of heart failure cannot be inhibited by pharmacotherapy. In this matter, novel treatment options that address the abnormalities of the immune system may be a promising therapeutic alternative or supplement for patients with heart failure owing to DCM. Antiviral therapy
Innate production of interferons is associated with clinical recovery from viral infections. Exogenous interferons may be protective in chronic viral diseases. An uncontrolled, open-label Phase II study has shown that treatment with IFN-b1a induced viral clearance from myocardial tissue as well as improvement of left ventricular function in patients with reduced left ventricular ejection fraction (LVEF) and myocardial persistence of enteroviral and adeno genomes [41]. IFN-b may also improve survival in patients with enterovirus-associated cardiomyopathy [42]. These findings must be confirmed by large randomized Phase III studies. Immunosuppression
Controversial results have been obtained from studies of the effects of immunosuppression in patients with myocarditis and DCM. A clinical trial of immunosuppressive therapy for myocarditis included patients with histopathological diagnosis of myocarditis according to the Dallas criteria [43] and reduced LVEF (
