Correspondence *St Luke's Hospital, 55236, Panorama, Thessaloniki, Greece

Email ppetrakopoulou@yahoo.gr

The case

A 37-year-old man presented with palpitations that had developed 5 months earlier. The episodes occurred approximately once a week and lasted several seconds. He had experienced a viral infection 3 months before the onset of palpitations, but had not received any medication. The patient had no family history of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) or any other notable cardiovascular disorders. His personal medical history was unremarkable.

Physical examination revealed no abnormalities, and there were no unusual findings on electrocardiography. Echocardiography showed both ventricles to be of typical size and functioning normally. The patient was admitted for further investigation. More than 2,000 polymorphic premature ventricular beats—all with right bundle branch block (RBBB) or left bundle branch block (LBBB) morphologies—were recorded by 24 h Holter monitoring along with short nonsustained ventricular runs and polymorphic ventricular tachycardia (VT). Cardiac catheterization and MRI showed a small ventricular aneurysm located in the anterior wall of the left ventricle (Figure 1). Coronary artery disease was excluded by coronary angiography. Endomyocardial biopsy (EMBx) specimens obtained from the right ventricular (RV) septum showed no signs of acute or persistent inflammation, or fibrofatty or granulomatous infiltration. The patient was started on -blocker therapy (metoprolol 95 mg/day) and discharged with the working diagnosis of healed myocarditis.

Figure 1 Freeze frames from a functional MRI study performed on the patient at presentation.

The individual frames demonstrate four different angles of two respective heart loops. Impaired right-ventricular systolic function and dilation of the right ventricle are evident, and an aneurysm of the superior basal region of the left ventricle can be seen in the second image of each row (arrows).

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A few weeks later, the patient was readmitted to hospital owing to persistent ventricular arrhythmias and dizziness. Antiarrhythmic therapy was initiated (amiodarone 200 mg/day). This therapy had to be terminated 2 years later, however, owing to amiodarone-induced hyperthyroidosis. Cessation of this medication led to recurrence of the palpitations and VT, and the patient had to be rehospitalized a further year later.

A summary of the diagnostic investigations undertaken at this point and their key findings is provided in Box 1; representative electrocardiograms are shown in Figure 2. In light of this information, the patient was diagnosed with ARVD/C, despite the lack of family history for this condition. Focal ablation was performed at the RV outflow tract (RVOT). There was a marked improvement in symptoms, and the patient did not experience a recurrence of VT during the following 3 months. After this period, however, an episode of sustained VT with LBBB morphology was recorded during exercise testing. A repeat electrophysiological study was performed and two episodes of VT, both with a LBBB pattern not previously observed, were induced. Focal ablation at the RVOT was again performed and the patient was discharged on sotalol (80 mg thrice daily).

Figure 2 Typical electrocardiograms recorded from the patient 3 years after his initial presentation.

(A,B) at rest upon admission and (C,D) during exercise testing, demonstrating a sustained ventricular tachycardia.

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There was no recurrence of VT during the following 15 months, but the patient subsequently returned to hospital following an episode of syncope. At this point, 4 years and 9 months had passed since his initial presentation. Echocardiography showed progressive RV dilation and impairment of RV function, but left ventricular (LV) size and function were normal (Figure 3). The syncope was attributed to a recurrence of VT and an implantable cardioverter-defibrillator (ICD) was fitted. Sotalol treatment was continued.

Figure 3 Echocardiograms recorded from the patient 4 years and 9 months after his initial presentation—8 months before he underwent cardiac transplantation.

(A) Apical 4-chamber axis view and (B) parasternal short axis view images demonstrating dilation of the right ventricle and hypokinesia of the septum. The dilation led to progressive impairment of right ventricular function.

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The patient was readmitted to hospital 3 months later having developed dyspnea on moderate physical exercise. Echocardiography demonstrated that the disease had progressed and LV function had also become impaired (LV ejection fraction was around 40%). Electrocardiography recorded multiple ventricular premature beats and first-degree atrioventricular block (460 ms). Interrogation of the ICD confirmed these findings, and the single chamber ICD was subsequently replaced by a dual-chamber ICD. In light of the functional deterioration caused by the ventricular arrhythmias, amiodarone therapy was considered indispensable and the patient underwent thyroidectomy. Amiodarone therapy was recommenced, and a marked decrease of premature ventricular beats was noticed, along with an improvement in the patient's symptoms.

Four months later, the patient again complained of progressive dyspnea and recurrent palpitations. LV pump function was severely impaired (LV ejection fraction was around 20%). The patient was evaluated and listed for cardiac transplantation, which was performed 1 month later. Pathological study of the explanted heart revealed no evidence of ARVD/C, but numerous noncaseating granulomas consistent with cardiac sarcoidosis were observed (Figure 4). There was no fibrofatty replacement of the myocardium. The results of laboratory examinations—including measurements of erythrocyte sedimentation rate, C-reactive protein, antinuclear antibodies and angiotensin-converting-enzyme levels—were normal.

Figure 4 Examination of the explanted heart revealed findings that were typical of cardiac sarcoidosis.

(A) Histological specimen using hematoxylin and eosin staining demonstrating noncaseating granulomatous myocarditis (original magnification 200). (B) Photograph of the patient's right ventricle showing patchy and confluent fibrosis.

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After cardiac transplantation, standard immunosuppressive therapy with prednisolone (5 mg/day), tacrolimus (target blood trough levels 12–14 ng/ml) and mycophenolate mofetil (target blood trough levels 2.5–4.0 ng/ml) was started. Routine EMBx is being performed every 4–6 weeks to monitor for possible rejection in the first 2 years following the transplant. At 8-month follow-up no noncaseating granulomas had been observed, and no cardiovascular or pulmonary disorders were evident. Systolic and diastolic function of the graft were both normal, and no arrhythmic episodes had been documented.

Discussion of diagnosis

Sarcoidosis is a granulomatous disease that affects a number of different organ systems to varying degrees, but most often affects the lungs. Other susceptible sites include the heart, skin, eyes, reticuloendothelial system, kidneys and central venous systems. The condition is characterized by the presence of noncaseating granulomas in affected tissues. Despite extensive research, the etiology of sarcoidosis is unknown. The prevalence of this condition varies between geographical regions, and the disease can also be associated with particular families and racial subgroups.¹

Cardiac involvement in sarcoidosis can be a benign incidental finding or a life-threatening disorder.² Clinical symptoms of cardiac involvement are present in about 5% of all patients with sarcoidosis. The manifestations of cardiac sarcoidosis are nonspecific and depend upon the location and extent of granulomatous inflammation. Involvement of the ventricular septum and conduction system can lead to a variety of arrhythmias, including complete heart block and sudden cardiac death. Ventricular premature beats, nonsustained VT or sustained VT are present in up to 22% of patients with sarcoidosis.³ It is thought that sarcoid granulomas become foci for abnormal automaticity or interfere with ventricular activation and recovery,³ leading to the creation of an arrhythmogenic substrate. Supraventricular arrhythmias seem to be uncommon in sarcoidosis. Other cardiac manifestations are valvular dysfunction (mainly of the mitral valve), pericarditis, ventricular-wall aneurysm and heart failure. Both systolic and diastolic dysfunction can occur in the disease.¹

The diagnosis of cardiac sarcoidosis is difficult because of the nonspecific nature of the clinical manifestations. Electrocardiographic changes—most commonly repolarization abnormalities, arrhythmias and conduction disturbances—are found in approximately 50% of patients who have systemic sarcoidosis and no clinical evidence of cardiac involvement.² Echocardiography can be used to detect features of advanced cardiac sarcoidosis such as septal thinning, regional abnormalities in wall motion, pericardial effusion and diastolic dysfunction. Shimada et al. reported that gadolinum-DTPA (diethylene triamine pentaacetic acid)-enhanced MRI may be beneficial for noninvasive detection of cardiac sarcoidosis and for evaluating the effects of steroid therapy.⁴ Myocardial imaging with ²⁰¹ thallium is useful for the identification of myocardial involvement in sarcoidosis and for the exclusion of cardiac dysfunction secondary to coronary artery disease. EMBx can definitively establish the diagnosis of cardiac sarcoidosis—a positive result suggests extensive cardiac involvement and is associated with a shorter median survival.⁵ The diagnostic yield from the procedure is low, however, owing to the irregular distribution of the granulomatous process. Ardehali et al. demonstrated that only 25% of patients with clinical signs of sarcoidosis and cardiomyopathy have noncaseating granulomas.⁵

The patient described in this report progressed to end-stage heart failure, having initially been diagnosed with ARVD/C with LV involvement. Histological analysis of the explanted heart, however, showed typical signs of cardiac sarcoidosis. There had been no findings from earlier physical examinations, laboratory tests or radiological studies to indicate this diagnosis, and the initial EMBx had been negative for granulomatous infiltration. The diagnosis of cardiac sarcoidosis seems to explain the patient's history of arrhythmias, palpitations, syncope and worsening heart failure. In hindsight, the episode of first-degree atrioventricular block that occurred 5 months before transplantation, in combination with the development of left-sided heart failure, could have been considered more typical of sarcoidosis than ARVD/C. Cardiac MRI or even an EMBx could have been performed at this time to investigate the possibility of sarcoidosis. Histological examination following transplantation revealed that the granulomatous infiltration had spread throughout the part of the explanted heart being investigated, suggesting that the spread of infiltration was associated with the deterioration of the cardiac function.

ARVD/C, first described in 1977 by Fontaine et al., is an inherited cardiomyopathy characterized by RV dysfunction and ventricular arrhythmias.⁶ Patients with ARVD/C demonstrate fibrofatty replacement of the myocardium of the right ventricle—most commonly between the anterior infundibulum, RV apex and the RVOT—and histological confirmation of this process is required for a definitive diagnosis. Palpitations, syncope, arrhythmia of RV origin and sudden cardiac death are all common presentations. Diagnostic criteria have been proposed by the task force of the European Society of Cardiology and the International Society and Federation of Cardiology.⁷ A diagnosis of ARVD/C is made if two major criteria, one major and two minor criteria, or four minor criteria are observed. The patient presented here fulfilled the major criterion of having dilation and reduction of the RV ejection fraction, as documented on echocardiography, and also fulfilled three minor criteria by demonstrating T-wave inversion in leads V1 and V2 (Figure 2), more than 2,000 premature ventricular beats with RBBB or LBBB morphologies in combination with brief episodes of nonsustained VT, and a sustained VT with LBBB pattern and inferior axis that was observed during exercise testing.

There are several important differential diagnoses that should be considered in patients with ARVD/C (Box 2). Although it is not common that cardiac sarcoidosis mimics the symptoms of the condition, some cases have been reported previously.⁸ It is important in future cases that a suspicion of cardiac sarcoidosis be retained in patients who have been diagnosed with ARVD/C.

Treatment and management

Therapy with corticosteroids is recommended for patients with a clear diagnosis of cardiac sarcoidosis.³ Treatment aims to control inflammation and fibrosis in order to maintain cardiac structure and function. Studies involving patients with cardiac sarcoidosis suggest better survival rates among those treated with corticosteroids than those not treated.⁹ The optimum results were obtained among patients who began receiving treatment when they had an LV ejection fraction greater than 50%. Daily doses of 60–80 mg prednisolone are usually recommended at the beginning of therapy. Alternative agents such as chloroquine, hydroxychloroquine, ciclosporin and methotrexate might be useful in patients who do not respond to corticosteroids or develop side effects.¹⁰

A previous study suggests that steroid treatment could be effective in the treatment of VT caused by sarcoidosis.¹¹ This effect might help to differentiate sarcoidosis from ARVD/C, where corticosteroid therapy would not be expected to be beneficial. Programmed ventricular stimulation might be useful for the identification of patients with cardiac sarcoidosis who are at high risk for future arrhythmic events, and ICD therapy could be protective in patients who have spontaneous or inducible ventricular arrhythmias.¹²

Surgery is occasionally needed in patients with cardiac sarcoidosis in order to resect ventricular aneurysms and abolish ventricular arrhythmias. Cardiac transplantation might, however, be necessary in younger patients with severe heart failure. There are only a few reports of transplantation for cardiac sarcoidosis. A donor–recipient transmission of sarcoidosis¹³ and two reports of a recurrence of sarcoidosis in a transplanted heart are of special interest.^{14, 15} Postoperative surveillance using routine EMBx is of great importance, since the disease can recur after tapering of corticosteroids.

Conclusions

We describe a patient with cardiac sarcoidosis who was diagnosed with ARVD/C on the basis of his clinical symptoms and electrocardiography findings. Diagnosis of cardiac sarcoidosis can be difficult in patients with a false negative EMBx result, and the disease should be considered as a possible underlying cause of cardiomyopathies of unknown etiology. Once a clear diagnosis is established, corticosteroid therapy should be used to prevent compromise of cardiac structure and function.

Acknowledgments

P Petrakopoulou and M Greif contributed equally to the preparation of this article.

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Subject areas under which this article appears: Cardiomyopathy and heart failure | Pathology