Curr Heart Fail Rep (2015) 12:263–268 DOI 10.1007/s11897-015-0260-x
MANAGEMENT OF HEART FAILURE (T MEYER, SECTION EDITOR)
Small Steps for Idiopathic Giant Cell Myocarditis Jeffrey A. Shih 1 & Jennifer A. Shih 2
Published online: 17 April 2015 # Springer Science+Business Media New York 2015
Abstract Idiopathic giant cell myocarditis (IGCM) is a rare disease causing progressive myocarditis characterized by myocardial necrosis and giant cells. Patients often present with rapidly progressive heart failure, ventricular arrhythmias, and heart block. Without treatment, the disease often results in progressive pump failure requiring urgent cardiac transplantation or the need for mechanical circulatory support. The underlying pathophysiologic mechanisms are not yet defined but appear to involve genetics, autoimmune disorders, and possibly environmental factors such as viruses. Combined immunosuppressive regimens appear to prolong survival from death or cardiac transplant. Nevertheless, cardiac transplant is an effective treatment. The disease can recur in the transplanted heart resulting in death or the need for retransplant.
and necrosis leading to rapidly progressive heart failure. The first reported case of IGCM occurred in 1905 [1]. Subsequent cases and case series have been described providing some insight into the natural history and treatment. Endomyocardial biopsy and surgical myocardial biopsy over the last several decades have allowed earlier diagnosis of IGCM, whereas prior data were limited to post-mortem autopsy case series. We review the most recent literature pertaining to IGCM and include our own experiences with diagnosing and treating this rare disease (Fig. 1).
Epidemiology
This article is part of the Topical Collection on Management of Heart Failure
IGCM affects a broad age range from 16 to 70 years old with a mean age in the fifth decade of life [2••, 3••]. There may be a female predominance based on the registry from Kandolin et al., although there was no gender predilection in another larger registry [2••]. The incidence of IGCM is low and assessed mainly from autopsy studies. In one autopsy study carried out at Oxford, only three of 12,815 cadavers were affected [4]. A similarly low incidence of IGCM was reported in Japan at 0.007 % and India at 0.051 % [5, 6]. The true prevalence and life-time incidence is unknown in large part due to the difficulty in making the diagnosis and identifying patients who passed away outside the hospital from the disease.
* Jeffrey A. Shih [email protected]
Pathophysiology and Etiology
Keywords Myocarditis . Idiopathic giant cell myocarditis . Fulminant myocarditis . Giant cell myocarditis . Heart failure . Cardiogenic shock
Introduction Idiopathic giant cell myocarditis (IGCM) is a rare but often times fatal disease characterized by myocardial inflammation
Jennifer A. Shih [email protected] 1
University of Massachusetts, 55 Lake Avenue North, Worcester, MA 01655, USA
2
Emory University, 1605 Chantilly Dr. NE, Atlanta, GA 30324, USA
The cause of IGCM remains under investigation, but it is likely a complex, multifactorial process. Infection, autoimmune responses, and genetics have all been implicated in the pathogenesis of IGCM. Case reports suggest infections from
264
Fig. 1 Hematoxylin and eosin stain, 400×. Myocardial apical core specimen showing lymphocytic infiltration, eosinophils (arrow), multinucleated giant cells (arrow head), and myocyte destruction (courtesy of Michael Kiernan, M.D., Robert Salomon, M.D.; Tufts Medical Center)
human herpes virus [7], coxsackie B2 virus [8], parvovirus B19 [9], and mycobacterium tuberculosis [10] may play a role in the development of IGCM. Other observations suggest that IGCM may be caused by autoimmune responses triggered by a number of factors. In two registries of patients with IGCM, there appears to be an association with autoimmune disorders in 19 % of cases [2••, 3••]. Associated autoimmune disorders and inflammatory cond itions includ e in fla mmatory b owel d ise ase, cryofibrinogenemia, optic neuritis, fibromyalgia, hyperthyroidism, and hypothyroidism [2••]. Other published reports cite associations with Hashimoto’s thyroiditis [11], rheumatoid arthritis [2••], thymoma [12], myasthenia gravis [12], Takayasu’s arteritis, alopecia totalis, vitiligo, orbital myositis, discoid lupus erythematosus [11], autoimmune hepatitis, [11], Guillian-Barre syndrome [13], systemic lupus erythematosus [11], Sjogrens [13], and pernicious anemia [2••]. Antibodies that bind to cardiac myosin and cross-react with the beta-adrenergic receptor may form by molecular mimicry or epitope spreading [14]. In the Lewis rat model, experimental IGCM can be transferred to naive rats by injection of T lymphocyte cells that recognize cardiac myosin antigen [15]. Other evidence that may implicate autoimmunity in IGCM is partial clinical remission when patients are treated with combined immunosuppression [2••, 3••] as well as less aggressive recurrence of IGCM in post-cardiac transplant patients on maintenance immunosuppression [16]. Recurrent IGCM in the transplanted heart also responds well to increased immunosuppression as evidenced by improved histologic infiltrate and hemodynamics [17]. Elezkurtaj’s recent cellular and molecular analysis argues for a vasculitis process with distinctive sets of chemokines, toll-like receptors (TLR), and dendritic cells (DC) in IGCM. DC are an early mediator of inflammation in vasculitis. TLR5,
Curr Heart Fail Rep (2015) 12:263–268
TLR7, cytokine CCL20, and chemokine receptor 6 (CCR6) all have a role in vasculitic inflammation, and TLR5, TLR7, TLR8, CCL20, and CCR6 were significantly upregulated in patients with IGCM versus controls [18]. IGCM is also influenced by genetic factors. Kittleson et al., found 115 differentially expressed genes between IGCM and non-failing hearts with the majority of upregulated genes in IGCM [19]. These involved T cell activators of the Th1 subset [19]. Another study reported induction of IGCM by utilizing porcine cardiac myosin. IGCM was induced in some strains of experimental rats (Lewis, Dahl, Fisher rats) but not in brown Norway rats. It was most severe in Lewis rats correlating with major histocompatibility complex class II region differences between strains [20]. Asimaki showed a potential link between IGCM, cardiac sarcoidosis (CS), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Plakoglobin expression was diminished in IGCM, CS, and ARVC, but not in lymphocytic myocarditis (LM). IL-17 and TNF-alpha, thought to be mediators of granulomatous myocarditis, caused marked redistribution of plakoglobin signal from myocardial cell-cell junctional sites to intracellular sites [21]. Differences in sex may play a role in IGCM. Testosterone promotes myocarditis, including IGCM, through the soluble ST2 pathway. Soluble ST2, a member of the interleukin 1 receptor family, is higher in males versus females with IGCM. Increased soluble ST2 levels in male mice correlate with poorer heart function and a more severe myocarditis [22].
Clinical Features The presentation of IGCM can be variable, but it most often presents as heart failure. The heart failure can be progressive, resulting in cardiogenic shock and the need for mechanical circulatory support (MCS). Other presentations include varying degrees of atrioventricular nodal or infra-nodal heart block, ventricular tachycardia, and ventricular fibrillation. At times, the initial presentation can mimic an acute myocardial infarction. There are rare presentations including cardiac tamponade (based on author’s experience) and an atrial variant of IGCM. Larsen et al. reported six cases of atrial variant IGCM. Of the five patients who were diagnosed prior to autopsy, the majority of patients had atrial fibrillation, severe atrial dilation, and preserved ventricular function [23]. Several other cases of isolated atrial IGCM have been reported [24–27]. Table 1 lists the presenting features from the two largest IGCM registries combined.
Diagnosis The diagnosis of IGCM is suggested by typical clinical features such as rapidly progressive heart failure or
Curr Heart Fail Rep (2015) 12:263–268 Table 1
265
Most common presenting features of IGCM
Heart failure Ventricular tachycardia/ventricular fibrillation Heart block Pseudo-acute myocardial infarction
Kandolin et al. (N=32)
Cooper et al. (N=63)
Combined (N=95)
10 (31 %) 7 (22 %) 10 (31 %) 4 (13 %)
47 (75 %) 9 (14 %) 3 (5 %) 4 (6 %)
57 (60 %) 16 (17 %) 13 (14 %) 8 (8 %)
malignant ventricular arrhythmias, but tissue is required for a definitive diagnosis. The most common method for obtaining tissue is by right ventricular endomyocardial biopsy (EMB) or through surgical biopsy often obtained during implantation of a ventricular assist device (VAD). Left ventricular EMB can be performed but in practice is less commonly performed. The pathology of IGCM is characterized by multifocal or diffuse, predominantly CD8positive lymphocytic infiltrates, eosinophils, and multinucleated giant cells. Myocytolysis and necrosis is often evident where giant cells are present. The true sensitivity of right ventricular EMB for IGCM is unknown but estimated to be around 68–80 % depending on the patient series [3••, 28]. In some instances, cardiac magnetic resonance imaging (CMR) can help guide endomyocardial biopsy, but findings of late gadolinium enhancement are not specific for IGCM [29]. The pathologic features of IGCM have been compared to cardiac sarcoidosis. In contrast to IGCM, myocardial specimens from those with CS have inflammatory cells composed predominantly of CD4-positive lymphocytes, fewer eosinophils, and giant cells within non-necrotizing granulomas. Pathologic findings consistent with IGCM correspond to a 5-year transplant-free survival of 21.9 % compared to 69.8 % for CS [5, 30–32]. Therefore, distinguishing between IGCM and CS is critical not only for prognosis determination but also for treatment. The Heart Failure Society of America advises endomyocardial biopsy in the setting of malignant arrhythmias out of proportion to left ventricular dysfunction or in rapidly progressive clinical heart failure or ventricular dysfunction particularly if IGCM or cardiac sarcoidosis is suspected [33•]. Myocardial gene expression profiling has been utilized to help distinguish IGCM and cardiac sarcoidosis. The largest series describing this examined 10 patients with IGCM, 10 with cardiac sarcoidosis, and 18 with active myocarditis versus 80 controls. RT-QPCR identified variations in gene expression of cytokines, chemokines, cellular receptors, and proteins involved in mitochondrial energy metabolism that varied with the cardiac pathology. The specific gene profiles that were established allowed identification of tissue with giant cells and helped discriminate between IGCM and cardiac sarcoidosis [34].
Natural History The prognosis of IGCM is abysmal. The median survival from the onset of symptoms in the multicenter giant cell myocarditis treatment study group registry was 5.5 months with 89 % dying or requiring cardiac transplantation [2••]. In another 32 patient cohort, 47 % of patients died or required cardiac transplantation after symptom onset [3••]. Kaplan-Meier estimates of 1-year survival from death or cardiac transplantation range from 30–69 % [2••, 3••]. These data may underestimate the risk of death as some patients may die prior presentation to a medical facility.
Treatment Medical Therapy Standard heart failure treatment including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists as outlined by the major cardiovascular societies are indicated [33•, 35•]. However, caution must be exercised in the patient with IGCM due to the possibility of conduction disease and the frequent occurrence of hemodynamic instability. Much of the data with regards to treatment comes from case reports and case series. These data have shown prolonged survival free from cardiac transplant with various immunosuppressive regimens [36–39]. From 1995 to 1997, a multicenter registry of IGCM was collected comprising 63 patients with confirmed IGCM. Patients who received no immunosuppression had a median survival from the onset of symptoms of 3 months. Various immunologic therapies were given to a portion of the patients (33/63) including monotherapy with corticosteroids (11/63); azathioprine with corticosteroids (11/63); cyclosporine combined with corticosteroids (3/63) or azathioprine (5/63); or corticosteroids, azathioprine, and muromonabCD3 (OKT3) (2/63). In patients who received some sort of combined immunosuppressive regimen, survival was improved to 12.3 months versus 3 months (p=0.001) [2••]. In follow-up to this registry, a prospective randomized study was planned to assess the efficacy of a combined immunologic regimen on outcomes, cardiac histology, and safety. However, due to recruitment difficulties, the study design was
266
Curr Heart Fail Rep (2015) 12:263–268
amended and a prospective, observational study was conducted instead with 11 subjects enrolled. Few patients chose to be randomized in the original trial design and risk not receiving immunomodulating therapy. The study did randomize four patients over 4 years to cyclosporine and corticosteroids versus OKT3, cyclosporine, and corticosteroids. However, the sample size is too small to make significant conclusions about OKT3 [40•]. This prospective observational study did reinforce the findings from the IGCM registry data [2••] showing improved survival with combined immunosuppression. The 1-year survival free of death or transplant was 73 % [40•]. A second, smaller, single center retrospective registry from the University Central Hospital in Helsinki, Finland, showed similar results in patients diagnosed with IGCM from 1991 to 2011. The most common regimen in the 26 treated patients was a combination of cyclosporine, azathioprine, and corticosteroids (17/26; 65 %). However, other regimens included mycophenolate mofetil (MMF), methotrexate, OKT3, or gamma globulin. All patients with biopsy-proven IGCM received combination immunosuppression and at times a three drug regimen. Survival at 1 year free of death or transplant was 77 % [3••]. The optimal immunosuppression regimen and appropriate timing to begin treatment is ill-defined. The patients included in the three registries above were to some degree a select population. The prospective observational study by Cooper et al. excluded those patients diagnosed at the time of cardiac transplantation, VAD placement, or on autopsy [40•]. The retrospective registries did not capture patients who were more critically ill, those without a tissue diagnosis, or those patients who expired without an autopsy being performed. Nevertheless, the available data suggest a combined regimen utilizing dual therapy with cyclosporine and corticosteroids or triple therapy with cyclosporine, azathioprine, and corticosteroids may be successful at prolonging survival when initiated at the time of diagnosis or suspected diagnosis [2••, 3••, 40•]. Table 2 shows potential triple therapy regimens which are similar to regimens used early post-cardiac transplant. Table 2
Alternative immunosuppressive regimens including proliferation signal inhibitors [41], tacrolimus [38, 41], methotrexate [3••], imuran [2••, 3••, 39, 40•], and gamma globulin [3••] have been reported. These various therapies have been utilized in single or multiple case reports. Therapy targeted at T lymphocytes appears effective in successfully treating IGCM but particularly in combined regimens. The added benefit of cytolytic therapy in the form of monoclonal or polyclonal antibodies has been debated. OKT3 was the primary cytolytic agent utilized in both the retrospective registry and the prospective observational study by Cooper et al. [2••, 40•]. The registry from Kandolin et al. only included 1 patient who received OKT3. Given the lack of a control population, benefit from OKT3 cannot be definitively concluded. However, patients in the Helsinki registry in whom the majority did not receive OKT3 seemed to have similar outcomes to the patient’s in the other registries who did receive OKT3. Unfortunately, OKT3 recently has become unavailable due to the manufacturer discontinuing production and exhaustion of available supplies so further study is not possible. Two case reports of successful bridging to recovery with mechanical circulatory support and cytolytic therapy combined immunosuppression are available in the literature [38, 42]. This may indicate equivalent efficacy of polyclonal cytolytic therapy, however there is sparse data [43]. In the author’s experience, three cases of tissue-proven IGCM requiring mechanical circulatory support for progressive cardiogenic shock were unsuccessfully treated with polyclonal cytolytic therapy, and the patients went on to require cardiac transplantation. Isolated cases of failed therapies are unlikely to be submitted for publication. Perhaps those patients reported in the literature who were bridged with MCS and cytolytic therapy successfully were merely outliers. Device Therapy Three case reports were found in the literature describing successful bridge to recovery with mechanical circulatory support
Possible immunosuppressive regimens for treatment of IGCM. One drug is selected from each class
Drug class
Drug
Dose
Monitoring
Calcineurin inhibitor
Cyclosporine (modified) Tacrolimus Methylprednisolone Prednisone Imuran
25–50 mg every 12 h 0.5–1 mg every 12 h 500–1000 mg IV every 24 h 60–80 mg PO every 12 h 50–150 mg daily
Mycophenolate mofetil
1000 mg every 12 h
ATGAM Thymoglobulin
10–15 mg/kg/24 h 1.5 mg/kg/24 h
Cyclosporine trough level of 150–200 mcg/L by HPLC FK506 trough level 10–15 ng/ml Tapered Tapered Titrated down for WBC 50 % Titrated down for WBC 50 % Adjusted for CD3 counts
MANAGEMENT OF HEART FAILURE (T MEYER, SECTION EDITOR)
Small Steps for Idiopathic Giant Cell Myocarditis Jeffrey A. Shih 1 & Jennifer A. Shih 2
Published online: 17 April 2015 # Springer Science+Business Media New York 2015
Abstract Idiopathic giant cell myocarditis (IGCM) is a rare disease causing progressive myocarditis characterized by myocardial necrosis and giant cells. Patients often present with rapidly progressive heart failure, ventricular arrhythmias, and heart block. Without treatment, the disease often results in progressive pump failure requiring urgent cardiac transplantation or the need for mechanical circulatory support. The underlying pathophysiologic mechanisms are not yet defined but appear to involve genetics, autoimmune disorders, and possibly environmental factors such as viruses. Combined immunosuppressive regimens appear to prolong survival from death or cardiac transplant. Nevertheless, cardiac transplant is an effective treatment. The disease can recur in the transplanted heart resulting in death or the need for retransplant.
and necrosis leading to rapidly progressive heart failure. The first reported case of IGCM occurred in 1905 [1]. Subsequent cases and case series have been described providing some insight into the natural history and treatment. Endomyocardial biopsy and surgical myocardial biopsy over the last several decades have allowed earlier diagnosis of IGCM, whereas prior data were limited to post-mortem autopsy case series. We review the most recent literature pertaining to IGCM and include our own experiences with diagnosing and treating this rare disease (Fig. 1).
Epidemiology
This article is part of the Topical Collection on Management of Heart Failure
IGCM affects a broad age range from 16 to 70 years old with a mean age in the fifth decade of life [2••, 3••]. There may be a female predominance based on the registry from Kandolin et al., although there was no gender predilection in another larger registry [2••]. The incidence of IGCM is low and assessed mainly from autopsy studies. In one autopsy study carried out at Oxford, only three of 12,815 cadavers were affected [4]. A similarly low incidence of IGCM was reported in Japan at 0.007 % and India at 0.051 % [5, 6]. The true prevalence and life-time incidence is unknown in large part due to the difficulty in making the diagnosis and identifying patients who passed away outside the hospital from the disease.
* Jeffrey A. Shih [email protected]
Pathophysiology and Etiology
Keywords Myocarditis . Idiopathic giant cell myocarditis . Fulminant myocarditis . Giant cell myocarditis . Heart failure . Cardiogenic shock
Introduction Idiopathic giant cell myocarditis (IGCM) is a rare but often times fatal disease characterized by myocardial inflammation
Jennifer A. Shih [email protected] 1
University of Massachusetts, 55 Lake Avenue North, Worcester, MA 01655, USA
2
Emory University, 1605 Chantilly Dr. NE, Atlanta, GA 30324, USA
The cause of IGCM remains under investigation, but it is likely a complex, multifactorial process. Infection, autoimmune responses, and genetics have all been implicated in the pathogenesis of IGCM. Case reports suggest infections from
264
Fig. 1 Hematoxylin and eosin stain, 400×. Myocardial apical core specimen showing lymphocytic infiltration, eosinophils (arrow), multinucleated giant cells (arrow head), and myocyte destruction (courtesy of Michael Kiernan, M.D., Robert Salomon, M.D.; Tufts Medical Center)
human herpes virus [7], coxsackie B2 virus [8], parvovirus B19 [9], and mycobacterium tuberculosis [10] may play a role in the development of IGCM. Other observations suggest that IGCM may be caused by autoimmune responses triggered by a number of factors. In two registries of patients with IGCM, there appears to be an association with autoimmune disorders in 19 % of cases [2••, 3••]. Associated autoimmune disorders and inflammatory cond itions includ e in fla mmatory b owel d ise ase, cryofibrinogenemia, optic neuritis, fibromyalgia, hyperthyroidism, and hypothyroidism [2••]. Other published reports cite associations with Hashimoto’s thyroiditis [11], rheumatoid arthritis [2••], thymoma [12], myasthenia gravis [12], Takayasu’s arteritis, alopecia totalis, vitiligo, orbital myositis, discoid lupus erythematosus [11], autoimmune hepatitis, [11], Guillian-Barre syndrome [13], systemic lupus erythematosus [11], Sjogrens [13], and pernicious anemia [2••]. Antibodies that bind to cardiac myosin and cross-react with the beta-adrenergic receptor may form by molecular mimicry or epitope spreading [14]. In the Lewis rat model, experimental IGCM can be transferred to naive rats by injection of T lymphocyte cells that recognize cardiac myosin antigen [15]. Other evidence that may implicate autoimmunity in IGCM is partial clinical remission when patients are treated with combined immunosuppression [2••, 3••] as well as less aggressive recurrence of IGCM in post-cardiac transplant patients on maintenance immunosuppression [16]. Recurrent IGCM in the transplanted heart also responds well to increased immunosuppression as evidenced by improved histologic infiltrate and hemodynamics [17]. Elezkurtaj’s recent cellular and molecular analysis argues for a vasculitis process with distinctive sets of chemokines, toll-like receptors (TLR), and dendritic cells (DC) in IGCM. DC are an early mediator of inflammation in vasculitis. TLR5,
Curr Heart Fail Rep (2015) 12:263–268
TLR7, cytokine CCL20, and chemokine receptor 6 (CCR6) all have a role in vasculitic inflammation, and TLR5, TLR7, TLR8, CCL20, and CCR6 were significantly upregulated in patients with IGCM versus controls [18]. IGCM is also influenced by genetic factors. Kittleson et al., found 115 differentially expressed genes between IGCM and non-failing hearts with the majority of upregulated genes in IGCM [19]. These involved T cell activators of the Th1 subset [19]. Another study reported induction of IGCM by utilizing porcine cardiac myosin. IGCM was induced in some strains of experimental rats (Lewis, Dahl, Fisher rats) but not in brown Norway rats. It was most severe in Lewis rats correlating with major histocompatibility complex class II region differences between strains [20]. Asimaki showed a potential link between IGCM, cardiac sarcoidosis (CS), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Plakoglobin expression was diminished in IGCM, CS, and ARVC, but not in lymphocytic myocarditis (LM). IL-17 and TNF-alpha, thought to be mediators of granulomatous myocarditis, caused marked redistribution of plakoglobin signal from myocardial cell-cell junctional sites to intracellular sites [21]. Differences in sex may play a role in IGCM. Testosterone promotes myocarditis, including IGCM, through the soluble ST2 pathway. Soluble ST2, a member of the interleukin 1 receptor family, is higher in males versus females with IGCM. Increased soluble ST2 levels in male mice correlate with poorer heart function and a more severe myocarditis [22].
Clinical Features The presentation of IGCM can be variable, but it most often presents as heart failure. The heart failure can be progressive, resulting in cardiogenic shock and the need for mechanical circulatory support (MCS). Other presentations include varying degrees of atrioventricular nodal or infra-nodal heart block, ventricular tachycardia, and ventricular fibrillation. At times, the initial presentation can mimic an acute myocardial infarction. There are rare presentations including cardiac tamponade (based on author’s experience) and an atrial variant of IGCM. Larsen et al. reported six cases of atrial variant IGCM. Of the five patients who were diagnosed prior to autopsy, the majority of patients had atrial fibrillation, severe atrial dilation, and preserved ventricular function [23]. Several other cases of isolated atrial IGCM have been reported [24–27]. Table 1 lists the presenting features from the two largest IGCM registries combined.
Diagnosis The diagnosis of IGCM is suggested by typical clinical features such as rapidly progressive heart failure or
Curr Heart Fail Rep (2015) 12:263–268 Table 1
265
Most common presenting features of IGCM
Heart failure Ventricular tachycardia/ventricular fibrillation Heart block Pseudo-acute myocardial infarction
Kandolin et al. (N=32)
Cooper et al. (N=63)
Combined (N=95)
10 (31 %) 7 (22 %) 10 (31 %) 4 (13 %)
47 (75 %) 9 (14 %) 3 (5 %) 4 (6 %)
57 (60 %) 16 (17 %) 13 (14 %) 8 (8 %)
malignant ventricular arrhythmias, but tissue is required for a definitive diagnosis. The most common method for obtaining tissue is by right ventricular endomyocardial biopsy (EMB) or through surgical biopsy often obtained during implantation of a ventricular assist device (VAD). Left ventricular EMB can be performed but in practice is less commonly performed. The pathology of IGCM is characterized by multifocal or diffuse, predominantly CD8positive lymphocytic infiltrates, eosinophils, and multinucleated giant cells. Myocytolysis and necrosis is often evident where giant cells are present. The true sensitivity of right ventricular EMB for IGCM is unknown but estimated to be around 68–80 % depending on the patient series [3••, 28]. In some instances, cardiac magnetic resonance imaging (CMR) can help guide endomyocardial biopsy, but findings of late gadolinium enhancement are not specific for IGCM [29]. The pathologic features of IGCM have been compared to cardiac sarcoidosis. In contrast to IGCM, myocardial specimens from those with CS have inflammatory cells composed predominantly of CD4-positive lymphocytes, fewer eosinophils, and giant cells within non-necrotizing granulomas. Pathologic findings consistent with IGCM correspond to a 5-year transplant-free survival of 21.9 % compared to 69.8 % for CS [5, 30–32]. Therefore, distinguishing between IGCM and CS is critical not only for prognosis determination but also for treatment. The Heart Failure Society of America advises endomyocardial biopsy in the setting of malignant arrhythmias out of proportion to left ventricular dysfunction or in rapidly progressive clinical heart failure or ventricular dysfunction particularly if IGCM or cardiac sarcoidosis is suspected [33•]. Myocardial gene expression profiling has been utilized to help distinguish IGCM and cardiac sarcoidosis. The largest series describing this examined 10 patients with IGCM, 10 with cardiac sarcoidosis, and 18 with active myocarditis versus 80 controls. RT-QPCR identified variations in gene expression of cytokines, chemokines, cellular receptors, and proteins involved in mitochondrial energy metabolism that varied with the cardiac pathology. The specific gene profiles that were established allowed identification of tissue with giant cells and helped discriminate between IGCM and cardiac sarcoidosis [34].
Natural History The prognosis of IGCM is abysmal. The median survival from the onset of symptoms in the multicenter giant cell myocarditis treatment study group registry was 5.5 months with 89 % dying or requiring cardiac transplantation [2••]. In another 32 patient cohort, 47 % of patients died or required cardiac transplantation after symptom onset [3••]. Kaplan-Meier estimates of 1-year survival from death or cardiac transplantation range from 30–69 % [2••, 3••]. These data may underestimate the risk of death as some patients may die prior presentation to a medical facility.
Treatment Medical Therapy Standard heart failure treatment including beta-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and aldosterone antagonists as outlined by the major cardiovascular societies are indicated [33•, 35•]. However, caution must be exercised in the patient with IGCM due to the possibility of conduction disease and the frequent occurrence of hemodynamic instability. Much of the data with regards to treatment comes from case reports and case series. These data have shown prolonged survival free from cardiac transplant with various immunosuppressive regimens [36–39]. From 1995 to 1997, a multicenter registry of IGCM was collected comprising 63 patients with confirmed IGCM. Patients who received no immunosuppression had a median survival from the onset of symptoms of 3 months. Various immunologic therapies were given to a portion of the patients (33/63) including monotherapy with corticosteroids (11/63); azathioprine with corticosteroids (11/63); cyclosporine combined with corticosteroids (3/63) or azathioprine (5/63); or corticosteroids, azathioprine, and muromonabCD3 (OKT3) (2/63). In patients who received some sort of combined immunosuppressive regimen, survival was improved to 12.3 months versus 3 months (p=0.001) [2••]. In follow-up to this registry, a prospective randomized study was planned to assess the efficacy of a combined immunologic regimen on outcomes, cardiac histology, and safety. However, due to recruitment difficulties, the study design was
266
Curr Heart Fail Rep (2015) 12:263–268
amended and a prospective, observational study was conducted instead with 11 subjects enrolled. Few patients chose to be randomized in the original trial design and risk not receiving immunomodulating therapy. The study did randomize four patients over 4 years to cyclosporine and corticosteroids versus OKT3, cyclosporine, and corticosteroids. However, the sample size is too small to make significant conclusions about OKT3 [40•]. This prospective observational study did reinforce the findings from the IGCM registry data [2••] showing improved survival with combined immunosuppression. The 1-year survival free of death or transplant was 73 % [40•]. A second, smaller, single center retrospective registry from the University Central Hospital in Helsinki, Finland, showed similar results in patients diagnosed with IGCM from 1991 to 2011. The most common regimen in the 26 treated patients was a combination of cyclosporine, azathioprine, and corticosteroids (17/26; 65 %). However, other regimens included mycophenolate mofetil (MMF), methotrexate, OKT3, or gamma globulin. All patients with biopsy-proven IGCM received combination immunosuppression and at times a three drug regimen. Survival at 1 year free of death or transplant was 77 % [3••]. The optimal immunosuppression regimen and appropriate timing to begin treatment is ill-defined. The patients included in the three registries above were to some degree a select population. The prospective observational study by Cooper et al. excluded those patients diagnosed at the time of cardiac transplantation, VAD placement, or on autopsy [40•]. The retrospective registries did not capture patients who were more critically ill, those without a tissue diagnosis, or those patients who expired without an autopsy being performed. Nevertheless, the available data suggest a combined regimen utilizing dual therapy with cyclosporine and corticosteroids or triple therapy with cyclosporine, azathioprine, and corticosteroids may be successful at prolonging survival when initiated at the time of diagnosis or suspected diagnosis [2••, 3••, 40•]. Table 2 shows potential triple therapy regimens which are similar to regimens used early post-cardiac transplant. Table 2
Alternative immunosuppressive regimens including proliferation signal inhibitors [41], tacrolimus [38, 41], methotrexate [3••], imuran [2••, 3••, 39, 40•], and gamma globulin [3••] have been reported. These various therapies have been utilized in single or multiple case reports. Therapy targeted at T lymphocytes appears effective in successfully treating IGCM but particularly in combined regimens. The added benefit of cytolytic therapy in the form of monoclonal or polyclonal antibodies has been debated. OKT3 was the primary cytolytic agent utilized in both the retrospective registry and the prospective observational study by Cooper et al. [2••, 40•]. The registry from Kandolin et al. only included 1 patient who received OKT3. Given the lack of a control population, benefit from OKT3 cannot be definitively concluded. However, patients in the Helsinki registry in whom the majority did not receive OKT3 seemed to have similar outcomes to the patient’s in the other registries who did receive OKT3. Unfortunately, OKT3 recently has become unavailable due to the manufacturer discontinuing production and exhaustion of available supplies so further study is not possible. Two case reports of successful bridging to recovery with mechanical circulatory support and cytolytic therapy combined immunosuppression are available in the literature [38, 42]. This may indicate equivalent efficacy of polyclonal cytolytic therapy, however there is sparse data [43]. In the author’s experience, three cases of tissue-proven IGCM requiring mechanical circulatory support for progressive cardiogenic shock were unsuccessfully treated with polyclonal cytolytic therapy, and the patients went on to require cardiac transplantation. Isolated cases of failed therapies are unlikely to be submitted for publication. Perhaps those patients reported in the literature who were bridged with MCS and cytolytic therapy successfully were merely outliers. Device Therapy Three case reports were found in the literature describing successful bridge to recovery with mechanical circulatory support
Possible immunosuppressive regimens for treatment of IGCM. One drug is selected from each class
Drug class
Drug
Dose
Monitoring
Calcineurin inhibitor
Cyclosporine (modified) Tacrolimus Methylprednisolone Prednisone Imuran
25–50 mg every 12 h 0.5–1 mg every 12 h 500–1000 mg IV every 24 h 60–80 mg PO every 12 h 50–150 mg daily
Mycophenolate mofetil
1000 mg every 12 h
ATGAM Thymoglobulin
10–15 mg/kg/24 h 1.5 mg/kg/24 h
Cyclosporine trough level of 150–200 mcg/L by HPLC FK506 trough level 10–15 ng/ml Tapered Tapered Titrated down for WBC 50 % Titrated down for WBC 50 % Adjusted for CD3 counts
