A case of biopsy-proven cardiac sarcoidosis without any other extracardiac manifestations

Summary

A 49-year-old woman was referred to our hospital for uncontrollable heart failure. She had never been diagnosed as having sarcoidosis. Chest X-ray showed cardiomegaly without bilateral hilar lymphadenopathy. Echocardiography showed diffuse hypokinesis of the left ventricle mimicking idiopathic dilated cardiomyopathy. No specific manifestations implying sarcoidosis were observed. On cardiac catheterization, coronary angiograms were normal, whereas concurrent routine endomyocardial biopsy showed foci of non-caseating granuloma, indicating sarcoidosis. Pathological finding was the only clue to diagnose cardiac sarcoidosis among our standard examinations for heart failure. No other additional investigations found any extracardiac features of sarcoidosis. All serological and immunological examinations were within normal range. This is a challenging case of biopsy-proven cardiac sarcoidosis without any other extracardiac involvement.

Introduction

Cardiac involvement in patients with sarcoidosis (cardiac sarcoidosis) is associated with poor prognosis. Appropriate therapies may prevent the progression of the involvement, but early and precise diagnosis is still challenging. A report of 320 autopsied cases of sarcoidosis in Japan [1] revealed that mortality relating to cardiac sarcoidosis was found in 150 cases of the 194 sarcoidosis-related deaths, but an ante mortem clinical diagnosis had been made in only 40 cases (26.7%). One of the major problems that make diagnosis difficult is that no conventional imaging techniques are sensitive enough to detect myocardial involvement. A more serious one is that some of the patients have cardiac-predominant disease without any other characteristic extracardiac features [2]. We report such a challenging case of biopsy-proven cardiac-predominant sarcoidosis without any other extracardiac manifestations.

Case report

A 49-year-old Japanese woman was referred to our hospital for uncontrollable heart failure. She complained of progressive fatigue and dyspnea on effort. She had never been diagnosed with sarcoidosis. On physical examination, blood pressure was 114/82 mm Hg and pulse was regular with 74 bpm. Her height was 151.5 cm and weight 58.9 kg. Her New York Heart Association (NYHA) class was III. Her breath sounds were normal. She had an abnormal third heart sound, but no murmurs. No obvious pretibial or facial edema was noted. Chest X-ray showed cardiomegaly with a cardiothoracic ratio of 0.55 without bilateral hilar lymphadenopathy (Fig. 1A). A 12-lead electrocardiogram (ECG) showed normal sinus rhythm, left axis deviation, abnormal Q in V_1–3, and intraventricular conduction disorder (QRS width: 152 ms; Fig. 1B, left panels). A holter ECG monitoring during 24 h showed 2274 beats of ventricular premature contraction with one triplet. No atrioventricular block was seen. Two-dimensional echocardiography showed enlarged left ventricle (LV); end-diastolic dimension (EDD) was 67 mm. Diffuse hypokinesis of the LV with ejection fraction (EF) of 34% was shown without thinning of the LV wall. On laboratory data, serum brain natriuretic peptide was increased to 254 pg/ml.

Figure 1.

(A) Chest X-ray showed cardiomegaly. Bilateral hilar lymphadenopathy was not observed. (B) 12 lead electrocardiograms (ECG) and echocardiographic data recorded on admission and 3 years after. An ECG on admission (left panels) demonstrated sinus rhythm with heart rate of 78 bpm, left axis deviation, abnormal Q in V_1–3, and intraventricular conduction disturbance with configuration of complete right bundle branch block (QRS width: 152 ms). No significant change occurred during 3 years. LV, left ventricle; EDd, end-diastolic dimension; EDs, end-systolic dimension; EF, ejection fraction.

Getting well due to standard therapy for heart failure, she underwent cardiac catheterization. Right heart catheterization revealed normal pulmonary capillary wedge pressure (mean: 4 mm Hg) and slightly reduced cardiac index (2.18 l/min/m²). Coronary angiograms were normal, but left ventriculography showed a diffuse reduction in LV motion especially at the anterolateral and apical wall. Concurrent myocardial biopsy of the right ventricular (RV) septum was done routinely for investigation of LV dysfunction, and then histological findings showed foci of non-caseating granuloma in the subendothelial layer and interstitial tissue, indicating cardiac sarcoidosis (Fig. 2).

Figure 2.

Hematoxylin-eosin staining of the myocardium from ventricular septum showed foci of non-caseating granuloma in the subendothelial layer and interstitial tissue (arrows). Scale bar, 100 μm.

After diagnosing sarcoidosis histopathologically, we assessed severity and range of the organ involvement. First, severity of the cardiac involvement was estimated. Myocardial scintigraphy using ²⁰¹Tl-Cl showed patchy persisting perfusion defect in the heart (Fig. 3A). Cardiac magnetic resonance imaging with gadolinium enhancement represented delayed myocardial enhancement strongly in the septal, and also in anterior, inferior, and posterior wall of LV (Fig. 3B). On the other hand, screening of extracardiac lesions by chest CT could not point out hilar or mediastinal lymphadenopathy. Abdominal echography and ⁶⁷gallium scintigraphy (Fig. 3C) also demonstrated almost normal findings. Pulmonary function test was normal (%vital capacity 115.2%, forced expiratory volume 1.0% 88.47%). Cutaneous and ophthalmologic complications were denied by each specialist. All serological examinations, the concentration of IgG (1450 mg/dl), angiotensin-converting enzyme (13.5 U/l), and lysozyme (7.6 μg/ml) were within the normal range. Tuberculin skin testing was positive.

Figure 3.

(A) Myocardial scintigraphy with ²⁰¹Tl-Cl showed perfusion defect at anteroseptal, septal, and apical wall. (B) Cardiac magnetic resonance imaging with gadolinium enhancement represented delayed myocardial enhancement most strongly in the septal, and also in anterior, inferior, and posterior wall of LV (arrows). (C) ⁶⁷Gallium scintigraphy showed negative finding. LV, left ventricle; RV, right ventricle.

She had received standard medication for heart failure with furosemide, spironolactone, imidapril, carvedilol, and digitalis. Then, we added prednisolone to prevent progression of sarcoidosis. Initial dose was 30 mg, and gradually tapered. Steroid therapy did not worsen the state of heart failure. When the patient was discharged, her NYHA functional class was improved to II.

Three years later, steroid therapy (prednisolone 5 mg/day) is continuing. Repeated ECG and echocardiograms showed no remarkable changes (Fig. 1B). She is almost fine and preserved the activity of daily life by herself.

Discussion

Cardiac sarcoidosis is clinically important because of poor prognosis and relatively high risk of sudden death. In Japan, this disease is more common than in the West [3] and responsible for as many as 85% of deaths from sarcoidosis [4]. On the other hand, it has been reported that steroids suppress inflammation and progression of fibrosis leading to significant improvement in survival [5]. Therefore, early recognition of cardiac involvement is crucial. But ante mortem diagnosis of cardiac involvement has been difficult, because clinical manifestations are often non-specific, and sensitivity and specificity of cardiac modalities are limited. A more serious problem is that approximately 5% of patients would have cardiac-predominant disease and present without major characteristic extracardiac features [2]. In such cases, it is hard to recognize the real etiology of their failed hearts.

In our case, her clinical manifestation on first admission was heart failure with LV systolic dysfunction mimicking idiopathic dilated cardiomyopathy. General physiological findings and standard examinations for heart failure did not imply sarcoidosis at all. Therefore, in her clinical course, routine endomyocardial biopsy was the only chance to diagnose her disease precisely. In general, biopsy is a conventional and specific method to diagnose cardiac sarcoidosis, but may lack sensitivity as a result of sampling error, because cardiac infiltration is usually patchy and focal [6]. In our case, broad and severe infiltration to RV septum, as our cardiac magnetic resonance imaging (MRI) clearly showed, might fortunately support us to get affected tissues. To detect such a clinically challenging disease as precisely as possible, a more sensitive and systematic strategy must be established. Nowadays, new imaging techniques, such as cardiac MRI [7] and fluorodeoxyglucose positron emission tomography (¹⁸F-FDG-PET) [8], are developing. Cardiac MRI was useful for us even after diagnosis histopathologically, because it could let us know the range of involvement. But, if performed earlier, those images would have played a much more crucial role for the process of diagnosis. ¹⁸F-FDG-PET might also have provided more accurate information about her illness, because it is reported to be more sensitive to scan not only cardiac sarcoidosis but also systemic lesions than ⁶⁷gallium scintigraphy [9]. A recent report suggested the usefulness of chest CT scan to detect mediastinal lymphadenopathy [10], whereas her lymph nodes were almost normal. It is sure that possibilities of minimal extracardiac invasions were not completely denied by our available investigations. However, there may be additional supporting evidence that no newly developing lesions have been detected outside of her heart during follow-up period.

To treat cardiac sarcoidosis, we added prednisolone to her medication for heart failure. As above, steroid therapy is reported to prevent progression of sarcoidosis and improve survival rates [5]. In fact, no remarkable exacerbation was shown by her ECG and echocardiographic data during these 3 years. On the other hand, it also has harmful side effects of water and salt retention on heart failure. Moreover, it does not seem to reduce the incidence of ventricular arrhythmias [11]. So, even after induction of this therapy, close outpatient observation was required to prevent worsening of heart failure or sudden cardiac death.

In conclusion, this case emphasizes that some patients with cardiac sarcoidosis have no any other extracardiac features. It is supposed to be a relatively rare case, not due to low morbidity but lack of appropriate strategy to detect latent patients. Recently, novel guidelines for diagnosis and treatment of myocarditis were published, which highlighted cardiac sarcoidosis as one specific type of myocarditis, and the value of cardiac MRI as an effective means of diagnosis [12]. Further efforts are required to reveal this lethal, but preventable disease.