Unraveling the Uncommon: A Case Report of Giant Cell Myocarditis and Examination of Existing Literature

Background

Idiopathic giant cell myocarditis (IGCM) is a rare disease causing progressive myocarditis characterized by myocardial necrosis and giant cells [1]. The incidence of IGCM is low and assessed mainly from autopsy. In autopsies from Japan and India, the incidence rate was 0.007% and 0.051% respectively [2,3]. This disease occurs in otherwise healthy young and middle-aged adults and leads to rapidly progressive heart failure in many cases [1]. It has been identified as a distinct entity from cardiac sarcoidosis, rheumatic heart disease, and Wegener granulomatosis [4].

The etiology of IGCM remains unknown, and other causes of myocarditis need to be ruled out before making a presumptive diagnosis. Among these other causes, viral infections are the most common cause of myocarditis, and examples of viruses that lead to this condition include human herpes virus (HHV), coxsackie B2 virus, hepatitis, HIV, and parvovirus B-19 infection [5–7]. Other potential etiologies include but are not limited to bacterial, fungal, and protozoal infections, as well as hypersensitivity reactions to drugs and other autoimmune disorders, such as inflammatory bowel disease, rheumatoid arthritis, thyroiditis, and vasculitis [5–7].

Presentation can vary and range from palpitations, fainting episodes, and, in some cases, sudden death, possibly from ventricular arrhythmias or high-grade atrioventricular heart block[8]. Patients with IGCM typically exhibit symptoms of progressive heart failure despite optimal treatment, which inexorably advances to either death or transplantation, with a rate of 70% at 1 year [5,9]. IGCM should be considered in all cases of unexplained dilated cardiomyopathy, particularly in young adults.

We present a case of a 65-year-old patient who presented with features of acute progressive heart failure despite medical treatment, due to IGCM. A review of the natural history and treatment of IGCM is also presented.

Case Report

A 65-year-old woman with a past medical history of atrial fibrillation status post ablation, hypertension, asthma, obstructive sleep apnea, prior diagnosis of colorectal adenocarcinoma (not treated), and hyperlipidemia presented to the Emergency Department with concerns of sudden onset shortness of breath and palpitations. She also described orthopnea and swelling of the lower extremities for 2 weeks prior to presentation. Laboratory workup was remarkable for high N-terminal pro-brain natriuretic peptide levels, microcytic anemia, and sub-clinical hypothyroidism. A chest X-ray revealed a small right pleural effusion, with partial right lower lobe atelectasis and cardiomegaly (Figure 1), while computed tomography pulmonary angiogram was negative for pulmonary embolism. A transthoracic echocardiogram (TTE) was obtained, which showed an ejection fraction of 40% to 45%, normal right ventricular systolic function, and hyperkinesis of the mid to apical walls, with basal hypokinesis. This was followed by a left heart catheterization, which showed no significant coronary artery disease (Figure 2).

During her hospitalization, her clinical course was further complicated with an episode of tachycardia-induced hypotension. An electrocardiogram at that time showed a wide complex tachycardia, at a rate of approximately 200 beats per min. This was consistent with ventricular tachycardia (Figure 3), which was treated with synchronized cardioversion, leading to subsequent reversion to sinus rhythm. She continued to have several episodes of non-sustained ventricular tachycardia, and a decision was made to start an amiodarone intravenous (i.v.) infusion.

An extensive workup to delineate the possible underlying etiology of her presentation was pursued. Blood cultures and tests for COVID-19, influenza, respiratory syncytial virus, HHV, HIV, hepatitis B/C serologies, and interferon gamma release assay were negative, ruling out infection. Immunologic studies revealed normal rheumatoid factor levels of <13, elevated acute phase reactants (C-reactive protein level of 39.7 mg/L [reference range, <5 mg/L] and erythrocyte sedimentation rate of 60 mm/h [reference range, <20 mm/h]), normal C3 and C4, negative antinuclear antibody, and antineutrophil cytoplasmic antibodies and unremarkable serum protein electrophoresis.

Considering her newly diagnosed non-ischemic cardiomyopathy and no ascertained underlying etiology, she underwent cardiac magnetic resonance imaging (CMR), which revealed severe systolic dysfunction and dilated cardiomyopathy, severe global hypokinesis (Video 1), with patchy areas of biventricular late gadolinium enhancement in multiple territories, including the left ventricular apex, lateral wall, and posterior right ventricle insertion, as well as diffuse interstitial fibrosis or edema, suggestive of non-ischemic infiltrative etiology (Figures 4, 5). A shared discussion between the patient and a multidisciplinary team led to a decision to undergo endomyocardial biopsy to help identify the etiology of her disease. Right ventricular endomyocar-dial biopsy revealed an inflammatory infiltrate of lymphocytes and eosinophils, with interspersed multi-nucleated giant cells, consistent with GCM, along with foci of myocyte necrosis. There were no granulomas or amyloid deposits (Figure 6).

She was started on combined immunosuppression therapy, with prednisone and cyclosporine. TTE at 1 week later showed improved contractility of the basal segments, the apex was no longer hyperdynamic, and her ejection fraction was noted to be 35% to 40%. In view of her increased risk of sudden cardiac death, an implantable cardioverter-defibrillator (ICD) was placed for secondary prevention. Left-ventricular assistance device implantation was discussed as a possible future treatment for the patient, as she was not a candidate for cardiac transplant, owing to her comorbidities. She was continued on guided-directed medical therapy (GDMT) for heart failure and was discharged home with cardiology follow-up.

Two months after discharge, she returned to the Emergency Department with concerns of palpitations, progressive lower extremity edema, and orthopnea. ICD interrogation revealed multiple episodes of non-sustained ventricular tachycardia and an episode of polymorphic ventricular tachycardia. The recurrent arrhythmias were thought to be secondary to inadequate immunosuppression; therefore, she was started on a pulse dose of methylprednisolone (1 g i.v. for 3 days) and azathioprine 200 mg daily (1.5 mg/kg/day) and was continued on amiodarone 200 mg daily orally. Following treatment initiation, she reported improvement of her symptoms, and a repeat TTE showed improvement in ejection fraction to 45% to 50%. No further episodes of non-sustained ventricular tachycardia were noted on telemetry monitoring, and she was discharged home on triple immunosuppression therapy, with prednisone 60 mg daily followed by a taper, cyclosporine 75 mg twice daily, and azathioprine 200 mg daily.

An outpatient positron emission tomography (PET) scan vs repeat endomyocardial biopsy was recommended to assess for resolution of inflammation and response to therapy. However, her clinical course was later complicated by multiple readmissions in the setting of heart failure exacerbations and opportunistic infections, secondary to profound immunosuppression treatment. The patient and her family ultimately decided to pursue hospice care, and therefore her ICD was turned off, and she subsequently died (Figure 7).

Discussion

We present a case of a 65-year-old female patient that presented to the hospital with symptoms of rapidly progressing nonischemic cardiomyopathy of unclear etiology who later received a diagnosis of IGMC. IGCM is one of the causes for refractory cardiac failure, as seen in this case, that should prompt clinicans to purse an endomyocardial biopsy. These steps would allow clinicians to achieve an early diagnosis and discuss the possibility of destination therapy with heart transplant.

IGCM is a rare and rapidly progressive autoimmune condition that affects relatively young and middle-aged adults who presents with cardiac failure or arrhythmias [5,10]. In the largest multicenter international registry, consisting of 63 patients with IGCM, the mean age at diagnosis was 42.6 years, with a age range of 16 to 69 years (like the case of our patient), with no sex predominance [5]. The exact underlying pathophysiology of IGCM is not well understood but is thought to be due to a T-cell-mediated inflammation of the heart muscle resulting in an acute inflammatory cardiomyopathy [11]. Antibodies capable of binding to cardiac myosin and exhibiting cross-reactivity with the beta-adrenergic receptor can arise through molecular mimicry or epitope spreading and can induce an antibody-mediated cAMP-dependent protein kinase A cell signaling activity in heart cells, leading to cell necrosis and damage [12].

The clinical manifestations of IGCM are heterogeneous and consist of a spectrum ranging from acute decompensated heart failure to cardiogenic shock requiring mechanical support and transplantation [7]. Electrophysiologic abnormalities such as high degree atrio-ventricular block and ventricular tachyarrhythmias are common and can be the initial presenting symptom or develop over the course of the disease [13]. In our case, the patient presented to the hospital with new-onset heart failure, in keeping with these findings, and subsequently developed multiple episodes of ventricular tachycardia, requiring ICD placement. In a review by Kandolin et al, approximately 59% of patients experienced sustained ventricular tachyarrhythmias [14]. Another study consisting of 51 patients with IGCM also reported a composite incidence of sudden cardiac death or ventricular arrythmia of 22% at 1 year [6,13]. Clinical manifestations of IGCM are commonly seen in other inflammatory cardiomyopathies, and the differentials for IGCM include, but are not limited to, cardiac sarcoidosis and lymphocytic and eosinophilic myocarditis [15].

Establishing a diagnosis of IGCM can be challenging, and conventional diagnostic tools, such as 12-lead electrocardiogram, cardiac biomarkers, and echocardiography, might only reveal nonspecific findings, which are seen in other causes in other causes of ischemic cardiomyopathy [15]. There is limited data on the use of CMR in patients with IGCM, owing to the rarity and high mortality associated with the disorder. CMR appearance of IGCM and cardiac sarcoidosis is highly similar, including evidence of multifocal late gadolinium enhancement and the presence of the “hook sign” (prominent involvement of the anteroseptal and inferoseptal insertion points of the right ventricle, with direct and contiguous extension across the septum into the right ventricle), which makes differentiating between the 2 rare entities solely based on CMR challenging [16,17]. Furthermore, CMR cannot differentiate IGCM from cardiac sarcoidosis, which has similar clinical manifestations to IGCM, such as heart failure, heart block, and ventricular tachyarrhythmias [18]. Similarly, a TTE can be used as the first-line diagnostic tool in patients with clinically suspected myocarditis, to strengthen the initial clinical suspicion and rule out other possible differential diagnosis. However, a TTE cannot differentiate between IGCM and cardiac sarcoidosis [19]. Therefore, IGCM is a pathologic diagnosis and requires an endomyocardial biopsy.

The sensitivity of the first endomyocardial biopsy is only 68%; however, this increases to 93% after the third biopsy [14]. This not only increases morbidity due to the high risk of complications from the procedure but also highlights the challenges clinicians face when trying to make this diagnosis, especially in a rural setting or non-resource-rich locations. Biopsy results that are characteristic of IGCM include the presence of widespread or multifocal infiltrates consisting of lymphocytes, histiocytes, and multinucleated giant cells, frequently in association with myocyte necrosis and eosinophils [1]. It is important to note that the diagnosis requires the absence of granulomas, which would be suggestive of cardiac sarcoidosis [7]. An accurate pathologic diagnosis is critical to determine long-term management and prognosis. Studies have shown that the prognosis of IGCM is significantly worse than that of cardiac sarcoidosis, as patients with cardiac sarcoidosis are noted to have a 5-year transplant-free survival of 69.8% vs 21.9% for IGCM patients [20]. Heart transplant is currently the best therapeutic option in patients with advanced IGCM or when aggressive immunosuppressive treatment fails. However, increased risk of early acute cellular rejection and disease recurrence (ranging between 0% and 15%) have been reported, and the prognosis following heart transplantation in IGCM remains unclear [21].

Patients with IGCM should be initiated on standard GDMT, as indicated for heart failure, and up-titrated as tolerated. Patients presenting with ventricular tachyarrhythmias and those with an ejection fraction <35% despite 3 to 6 months of GDMT, should be considered for ICD implantation, as was the case of our patient [22]. Immunosuppressive therapy plays an integral role in the management of patients with IGCM. In a multi-center IGCM study, a significant improvement in survival was reported with the use of combination immunotherapy consisting of cyclosporine, azathioprine, and corticosteroids [5]. Furthermore, Kandolin et al investigated the role of combination immunosuppression in 26 biopsy-proven IGCM patients and found that combined immunosuppression resulted in a transplant-free survival of 52% at 5 years, but patients were still susceptible to ventricular tachyarrhythmias [14]. Moreover, a prospective multicenter IGCM trial of immunosuppression including cyclosporine and steroids for acute, microscopically confirmed IGCM, showed that after 4 weeks of treatment, the degree of necrosis, cellular inflammation, and giant cells decreased (P=0.001) in serial endomyocardial biopsies [12]. Insufficient data is available to offer clear guidance on long-term immunosuppressive strategies for sustaining remission in IGCM. Nevertheless, current evidence leans toward maintaining immunosuppression using a combination of cyclosporine and azathioprine, with or, if possible, without a minimal dose of prednisone [14]. However, despite GDMT and combined immunosuppression, a significant number of patients with IGCM develop refractory heart failure and/or cardiogenic shock requiring mechanical support and heart transplantation [8].

Finally, regarding follow-up of these patients to assess response to therapy, PET scanning has shown utility in characterizing myocarditis [13]. When performed with fluorine-18 fluorodeoxyglucose (FDG) it has the unique ability to depict metabolically active disease, and in this respect, in addition to CMR, it might provide complementary information on disease progression. While healthy tissue will show normal perfusion, inflamed myocardium shows decreased perfusion and increased 18F-FDG up-take. Activated leukocytes, especially macrophages, are known to express high levels of glucose transporters, which result in rapid accumulation of 18F-FDG at the site of inflammation [21]. Additionally, FDG-PET can be helpful in identifying lymph nodes as a target site for biopsy to rule out cardiac sarcoidosis, with which there can be substantial clinical overlap [22].

Conclusions

Because of the rarity and clinical heterogeneity of IGCM, its diagnosis can be challenging and can lead to a delayed or missed diagnosis. Rapidly deteriorating heart failure that is refractory to GDMT and associated with electrophysiological abnormalities, such as high-degree atrio-ventricular block and ventricular arrhythmias, should prompt clinicians to pursue an endomyocardial biopsy, which can aid in an early diagnosis of IGCM. Early evaluation of patients who present with features of fulminant acute myocarditis is crucial to facilitate workup for the possibility of a heart transplant or left-ventricular assistance device. While no concrete guidelines currently exist regarding the medical management of IGCM, all patients, especially those not candidates for transplant, should be initiated on combined immunosuppression. In summary, patients with IGCM require a comprehensive, multidisciplinary team to ensure thorough and effective care. However, despite medical therapy, it remains evident that without a transplant, most patients have a poor long-term prognosis and outcome.