Introduction

Contrary to granulomatous myocarditis, which is mostly part of a systemic granulomatous disease (tuberculosis, sarcoidosis, or hypersensitivity reaction), giant cell myocarditis is a histopathological diagnosis, nearly impossible to verify by clinical examination preoperatively (Table 1).

Table 1 Main causes of giant cell and granulomatous myocarditis
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Giant cell myocarditis is a rare and frequently fatal disorder, first described by Saltykow [1] in 1905 in a 37-year-old man dying suddenly after surgical drainage of an abscess. Until now, its etiology has not yet been fully elucidated. In the first half of twentieth century, borders between giant cell myocarditis and granulomatous myocarditis were not well defined, and names were used interchangeably leading sometimes to confusion. For differentiation, the presence of granulomas is the most important distinguishing mark.

Tesluk [2] was the first who separated the granulomatous lesions of sarcoidosis (Figs. 1 and 2) from a diffuse, nongranulomatous infiltrate, which he called giant cell myocarditis. The majority of giant cell myocarditis cases are clinically unrecognized, and primary diagnosis is confirmed at autopsy or in explanted heart specimens.

Fig. 1
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Gross appearance of cardiac sarcoidosis: cut surface of the left ventricular anterior wall with pale fibrotic areas

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Fig. 2
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a, b Cardiac sarcoidosis: heart specimens with non-necrotizing granulomas, multinuclear giant cells, interstitial fibrosis, and surrounding lymphocytic infiltration (hematoxilin and eosin staining, original magnification—a: 20-fold, b: 10-fold)

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The cause of giant cell myocarditis is not known but often presumed to be autoimmune. A total of 20 % of cases of giant cell myocarditis occur in individuals with other inflammatory or autoimmune disorders (Table 2), especially inflammatory bowel disease [3–9]. Some authors hypothesize an autoimmune origin with correlation to myasthenia gravis, chronic lymphocytic thyroiditis, and giant cell myositis [10, 11]. The tumor most commonly associated with giant cell myocarditis is thymoma, especially the spindle cell type [12]. The occurrence of giant cell myocarditis has even been described after high-dose interleukin-2 treatment for lymphoma, maybe as a result of cytokine imbalance [13]. Besides the broad spectrum of diseases that may be accompanied by giant cell myocarditis, it must be considered that giant cell reaction can also occur after surgery (e.g., valve replacement or coronary artery bypass grafting). Suture material may initiate the immune system to build granulomas with surrounding giant cells, phagocyting the foreign material (Fig. 3).

Fig. 3
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Multinuclear giant cells phagocyting suture material surrounded by lymphocytic infiltration. Heart specimens from a patient after antecedent coronary artery bypass surgery (hematoxilin and eosin staining, original magnification: 40-fold)

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Table 2 Disorders associated with giant cell myocarditis
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Material and methods

A total of 355 female and male patients received heart transplantation at the Department of Cardiac Surgery of the Medical University Innsbruck between January 1994 and December 2011. Explanted hearts were sent to the Department of Pathology. Heart specimens were fixed with 4 % phosphate-buffered formalin, dehydrated, paraffin embedded, cut into 2-μm-thick slides, stained with hematoxilin and eosin, and reviewed by experienced pathologists. In this study, we investigated preoperative and postoperative course, gross morphological changes, and histopathological features of seven heart transplant recipients suffering from giant cell and granulomatous myocarditis.

Results

Histopathological examination of explanted heart specimens of the 355 heart transplant recipients revealed 4 cases of giant cell myocarditis and 3 cases of granulomatous myocarditis (Table 3).

Table 3 Case descriptions
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None of these patients were transplanted due to the preoperative clinical diagnosis of giant cell or granulomatous myocarditis. The cause of transplantation was dilated cardiomyopathy (four patients), followed by ischemic heart disease (two patients) and solitary cardiac sarcoidosis without other organ involvement (one patient). Of the seven affected patients, one was female and six were male. Anamnestically, no autoimmune disorders were reported. Mean recipient age at transplantation was 45.5 ± 13.9 years in the giant cell myocarditis group (range, 35–66 years) and 52.7 ± 9.1 years in the granulomatous myocarditis group (range, 43–61 years). The median time of follow-up was 109.7 months (range, 3 days to 174 months).

Preoperatively, all patients suffered from mild to severe symptoms of heart failure (New York Heart Association class II–IV). In two patients, ventricular tachycardia was present; one patient received an implantable cardioverter-defibrillator 1 year before heart transplantation. Electrocardiographic findings were suggestive of myocardial infarction in one patient, and two other male patients suffered from atrial fibrillation.

Left ventricular ejection fraction was significantly reduced in both groups and ranged between 10 and 35 %. Additionally, the mitral valve was involved in three patients showing signs of mild to severe valvular insufficiency, and two patients showed tricuspid valve involvement. Two patients received ventricular assist devices as bridge to transplantation.

Common aspects between giant cell and granulomatous myocarditis include extended fibrosis and right and left ventricular hypertrophy. The main gross finding in both groups was endomyocardial fibrosis mainly localized in the left ventricle and interventricular septum. Mean heart weight for the granulomatous myocarditis group was 433.3 ± 121.6 g (range, 313–527 g), and mean heart weight for the giant cell myocarditis group was 476.3 ± 84.4 g (range, 405–580 g).

Extended endomyocardial fibrosis, disrupted by more or less inflammatory infiltrates, mainly composed of lymphocytes, plasma cells, giant cells, and non-necrotizing or necrotizing granulomas, was the main histological finding in both groups. A causative organism could not be verified.

Postoperatively, four patients are currently alive, and three heart transplant recipients of the giant cell myocarditis group died. A male heart transplant recipient developed Guillain-Barré syndrome due to cytomegalovirus reactivation 8 months after cardiac transplantation and died due to sudden cardiac death after recovery from pneumonia 2 years postoperatively. One patient died due to cerebral edema 3 days after heart transplantation, and another heart transplant recipient died because of cerebral and myocardial infarction after tricuspid valve replacement 11 years after transplantation.

None of these seven patients showed granulomas or giant cell reaction in any of the routinely performed post-transplant endomyocardial biopsies. The highest rejection belonged to grade 1R (ISHLT 2004).

Discussion

In general, most patients with giant cell or granulomatous myocarditis suffer from nonspecific symptoms like chest pain, fatigue, ventricular arrhythmia, or heart block, and in several cases, initial symptoms can mimic those of acute myocardial infarction [14], with a usually more fulminant course in the case of giant cell myocarditis.

Giant cell myocarditis, an oftentimes lethal disease, is characterized by progressive congestive heart failure, frequently associated with refractory ventricular arrhythmia and rapid deterioration—the time period from onset of the first symptoms to severe heart failure and cardiogenic shock is usually only a few days or weeks. Men and women are equally affected, with an average age of 43 years at the time of symptom onset.

In the late 1980s and 1990s, the average time from the start of symptoms to death or transplantation was only 5 months, and many patients died before they could be listed for heart transplantation. Even now, the mean interval from the time of diagnosis to death or cardiac transplantation is still 6 months. Survival beyond 1 year without heart transplantation is uncommon. Recurrence in the native heart occurs up to 8 years after initial diagnosis.

Cardiac magnetic resonance imaging and endomyocardial biopsy can be helpful in making the correct diagnosis and ensuring that timely adequate treatment is administered, but sampling error remains a significant limitation to the diagnostic accuracy of the endomyocardial biopsy [15]. Usually, four to six biopsy samples are routinely analyzed during a diagnostic procedure, but a negative result without any evidence of granulomas does not automatically exclude giant cell or granulomatous myocarditis because of the patchy pattern of both diseases.

Whereas the treatment of granulomatous myocarditis commonly consists of drugs used for the underlying disease (corticosteroids for sarcoidosis, three- and fourfold drug combination with rifampicin, ethambutol, and isoniacid for tuberculosis, methotrexat and gold for rheumatic disease, and antihistamines for hypertensitivity disease), the rapidly progressive course of giant cell myocarditis requires immediate therapeutic intervention, including standard pharmacologic therapy for congestive heart failure, tachyarrhythmias, heart block, and secondary hepatic and renal insufficiency.

Since the first report of the Multicenter GCM Study Group [14], the recommended treatment has been the triple combination of cyclosporine, prednisone, and azathioprine. Exceptionally, other immunosuppressive drugs like mycophenolate mofetil, methotrexate, or the T-cell antibody muromonab can be added or substituted for other agents [16].

The combined treatment with immunosuppressants improves the poor prognosis, and yield a median survival time of 12 months compared with 3 months for untreated affected patients. Nevertheless, some patients require mechanical circulatory support or heart transplantation within 1 year [17].

The implantation of a temporary or permanent pacemaker, an implantable cardiac defibrillator, intra-aortic balloon pumps, or ventricular assist devices to bridge the time until heart transplantation may be necessary. Although a bridge to transplant concept is unavoidable in most cases, in general, the time period to transplantation is short and ranges from a few days to weeks.

Transplantation remains an effective therapy for patients suffering from giant cell myocarditis, yielding a 5-year survival rate of 71 % despite a 20–25 % risk of recurrence in the allograft, with an usually fulminant clinical course and sometimes even fatal outcome [14, 18–20]. It has been estimated that one-third of the 25 % of recurrences may be lethal [21, 22].

Histologically, three phases of giant cell myocarditis (acute, healing, and healed) have been described and may coincide within a single heart. The acute phase usually consist of typically multifocal necrosis and widespread mixed inflammatory infiltrate composed of numerous multinucleated macrophagic giant cells, lymphocytes, histiocytes, plasma cells, and eosinophils. The healing phase consists of granulation tissue and collagen with macrophagic and myogenic giant cells and occasional lymphocytes. The histiogenesis of the giant cells is still discussed controversially. Maybe the derivation of giant cells is related to the type or phase of injury or the nature of the response evoked.

Although giant cell myocarditis is associated with autoimmune genesis in 20 % of patients, none of our patients suffered from additional autoimmune disease. In our study, patients with giant cell myocarditis were younger at heart transplantation than those with granulomatous myocarditis. None of our patients suffered from recurrence of giant cell or granulomatous myocarditis, and none of the surviving transplant recipients showed signs of severe allograft rejection in post-transplant endomyocardial biopsies. Three of the four patients suffering from giant cell myocarditis showed a complicated postoperative clinical course, and two of them died shortly after transplantation. In contrast, all three granulomatous myocarditis patients are currently alive.

Gross findings of explanted hearts did not significantly differ between the granulomatous myocarditis and the giant cell myocarditis group. Right and left ventricular hypertrophy and more or less expanded endomyocardial fibrosis were present in both groups. Because myocardial involvement in giant cell myocarditis is usually extensive, hearts of patients with acute clinical presentations are typically dilated with flaccid ventricular walls. The cut surface of the myocardium contains pale areas, which correspond to areas of intense inflammation. Scarring is not characteristic of the acute disease but may appear in hearts of patients with longer survival.

On the first sight, a relevant limitation of our study is the small number of patients in both groups, the giant cell myocarditis group and the granulomatous myocarditis group, but maybe this study can add some information to the course of both diseases. In general, the lack of data concerning long-term management of giant cell and granulomatous myocarditis patients highlights the need for continuing multicenter collaborative clinical and pathological investigations.

Conclusion

Giant cell myocarditis and granulomatous myocarditis are two different disorders, both characterized by worsening heart failure with a more fulminant course for giant cell myocarditis patients. Heart transplantation may be required for end-stage heart failure, but transplantation does not necessarily protect from recurrence of the disease.

In conclusion, our results suggest, in accordance with previously published studies, that giant cell myocarditis is a disease that affects younger persons and is characterized by poorer clinical outcome after cardiac transplantation and more severe post-transplant complications in comparison with granulomatous myocarditis. However, future studies are required to elucidate the pathogenetic, clinical, and therapeutic implications of our results.

Disclosure

This article was not supported by any fund. Informed consent was obtained from all patients for being included in the study. The study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Conflict of interest

C. Steger, D. Höfer, and H. Antretter declare that there is no conflict of interest.