Ventricular tachycardia as the first manifestation of cardiac sarcoidosis

Abstract

The case of a 32-year-old man with sustained ventricular tachycardia and hypotension is described. Following pharmacological treatment the patient switched to a sinus rhythm and was transferred to a university hospital for further diagnostic procedures and treatment. Cardiac catherisation ruled out underlying coronary artery disease, and cardiac MRI as well as echocardiography demonstrated a moderately reduced left ventricular ejection fraction, marked thickening of the interventricular septum and extensive intramural and epicardial infiltration of both ventricles. Endomyocardial biopsies were inconclusive; an implantable cardioverter defibrillator (ICD) was implanted in order to prevent a fatal arrhythmic event. Only repeated lymph node biopsies revealed typical findings of granulomatous disease, which together with the clinical course and the cardiac MRI findings strongly supported cardiac sarcoidosis. A few days after initiation of therapy with corticosteroids, the patient experienced the first of a number of ICD discharges, demanding aggressive anti-arrhythmic treatment regimen for the future.

BACKGROUND

Sarcoidosis is a multisystemic, granulomatous disease predominantly affecting the lungs. However, a broad spectrum of other organ involvement has been described, often concerning lymphatic tissue, skin, the central nervous system, the eyes and the heart.^1–3 Cardiac sarcoidosis seems to be a rare event in clinical findings but is far more frequent in pathology series.⁴ Myocardial infiltration linked with clinical and/or electrical findings has been responsible for about 50% of deaths in sarcoidosis patients in the past.⁵ Among patients dying from cardiac sarcoidosis, dysrhythmias and conduction disturbances have been identified as the predominant causes of death, followed by heart failure and rare events such as ventricle rupture or ischaemia related to granulomatous infiltrations.⁶ Diagnostic efforts and procedures aim for the early and reliable diagnosis of cardiac involvement in generalised sarcoidosis or the identification of granulomatous infiltration as the underlying cause of heart disease. Protecting patients from fatal arrhythmic events by implantation of device systems and initiation of an adequate anti-arrhythmic regimen as well as corticosteroid treatment before the occurrence of systolic dysfunction are of great importance,⁷ as is shown in the following case report.

CASE PRESENTATION

A previously healthy 32-year-old man attended the emergency room of a community hospital because of repeated emesis and palpitations. Upon presentation the patient was hypotensive (80/40 mm Hg) without signs of pulmonary oedema; his ECG displayed a broad complex tachycardia at a rate of 180/min. The ECG was interpreted as monomorphic ventricular tachycardia (fig 1A); in spite of systemic hypotension, initial treatment was with boluses of metoprolol iv. When this therapy resulted in no relevant changes in heart rate, a bolus of 25 mg ajmaline was administered iv. In response to this, the patient converted to sinus rhythm with remarkably low voltage QRS-complexes in the limb leads, an incomplete right bundle branch block and T-wave inversions in the inferior leads (fig 1B). Note that according to accepted international guidelines for patients with haemodynamically significant ventricular tachycardia, metoprolol is not the therapy of choice and ajmaline (a class IA anti-arrhythmic drug) has only a class IIA recommendation in stable patients with sustained monomorphic ventricular tachycardia.⁸ The initial laboratory results in our patient showed a positive troponin T (0.31 µg/l, reference limit 0.03 µg/l) and a mildly elevated creatinine kinase (219 U/l, reference limit 171 U/l). Serum electrolytes, in particular potassium and calcium, were within normal ranges, and there were no signs of systemic inflammatory response. The patient was transferred to the intensive care unit of the university hospital for further assessment. A review of the history and re-examination could not identify symptoms such as cough, haemoptysis, shortness of breath, fever, rash or iritis. The family history revealed a sister with Crohn’s disease but no history of cardiomyopathy or sudden death.

Figure 1.

(A) Admission ECG showing monomorphic ventricular tachycardia with a heart rate of approximately 180/min (paper speed 50 mm/s). (B) ECG following cardioversion showing right bundle branch block, T-wave inversion in the anterior leads and low limb lead voltages (paper speed 50 mm/s).

INVESTIGATIONS AND DIFFERENTIAL DIAGNOSIS

Echocardiography revealed normal dimensions for the left ventricle and atrium and a slightly enlarged right ventricle. The global ejection fraction of the left ventricle was mild to moderately reduced (LV-EF 45%) with a marked thickening of the inter-ventricular septum (19 mm) and regional hypokinesia in this area (fig 2); however, no other features of hypertrophic, hypertrophic obstructive or restrictive cardiomyopathy were present on echocardiography. Cardiac catherisation demonstrated unremarkable coronary arteries and also wall motion abnormalities in the area of the inter-ventricular septum. The next diagnostic step was contrast enhanced cardiac magnetic resonance imaging (cMRI) to investigate inflammatory changes and structural abnormalities of the left or the right ventricle. T1- and T2-weighted STIR- and FSE-sequences and cine MRI confirmed the septal thickening as well as the anterior and septal pronounced wall motion abnormalities of the left ventricle. The overall dimensions of the left ventricle were nearly normal (LV end-diastolic volume 91 ml/m², normal 53–112 ml/m²; LV end-systolic volume 49 ml/m², normal 15–45 ml/m²), however the LV ejection fraction was reduced to 46% (normal 55–73%). The right ventricle also displayed hypokinesia of the free wall (RV-EF 49%, normal 50–63%) and was markedly enlarged (RV end-diastolic volume 234 ml/m², normal 58–114 ml/m²; RV end-systolic volume 72 ml/m², normal 25–53 ml/m²); there were no further typical signs indicating features of arrhythmogenic right ventricular cardiomyopathy (ARVC). Furthermore, delayed gadolinium-DTPA contrast enhanced imaging demonstrated extensive infiltrative changes of the left ventricle, predominantly in the antero-septal and infero-septal segment, while the right ventricle showed diffuse infiltrations mainly in area of the free wall, reaching the right ventricular outflow tract (fig 3).

Figure 2.

Transthoracic echocardiography (GE, vivid 7, 4 MHz transducer) showing a parasternal long axis view demonstrating septal hypertrophy (end-diastolic image).

Figure 3.

Gadolinium-DTPA contrast enhanced cardiac MRI (GE, twin speed, 1.5 T) short axis view demonstrating late myocardial enhancement. Arrow heads indicate diffuse infiltration of the right ventricular free wall; arrows indicate several zones of left-ventricular intramural and epicardial late enhancement.

The differential diagnoses considered were myocarditis, perimyocardial involvement of Churg-Strauss syndrome, cardiac sarcoidosis, infiltration of the myocardium by malignant lymphoma, and other forms of cardiomyopathy including ARVC. A broad spectrum of microbiological testing including viral serology for cytomegalovirus, Ebstein-Barr virus and adeno-, entero-, herpes-, influenza- and parvovirus revealed no significant positive results; borrelia, toxoplasma and trypanosomal serology were all negative. Cardiovascular magnetic resonance (CMR)-guided endomyocardial biopsies of the right ventricle failed to demonstrate typical ARVC-related fatty fibrotic changes of the myocardium, mononuclear infiltration or other histological features typical for myocarditis, Churg-Strauss-specific eosinophilic infiltrates, giant cell granuloma as seen in sarcoidosis, infiltration of the myocardium by lymphoma or storage of amyloid, iron or other substances within the myocardium.

Given the demonstration of modest bihilar lymphadenopathy on chest x ray and a following CT thorax scan which also revealed enlarged hilar and mediastinal lymph nodes (fig 4), sarcoidosis was considered the main differential diagnosis. However, a bronchoscopy including endo-bronchial lavage identified only small numbers of lymphocytes; biopsies from the respiratory epithelium as well as an enlarged peribronchial lymph node were inconclusive, revealing haemorrhagic material only. Finally, levels of angiotensin-converting enzyme (ACE) and soluble interleukin-2-receptor (s-IL-2-R) as typical parameters of active sarcoidosis were within normal ranges.

Figure 4.

Chest x ray and CT thorax demonstrating bihilar and mediastinal lymphadenopathy.

In view of the inconclusive investigations, a repeat bronchoscopy was undertaken shortly after the patient was discharged from hospital. Immunohistochemistry of the repeated examination demonstrated typical findings of granulomatous disease in lymph node and respiratory epithelium (fig 5). Furthermore, differential blood count of the broncho-alveolar lavage showed an elevated ratio of CD4/CD8-positive lymphocytes (5.3, normal: 1–3.5). Taken together, these results suggested sarcoidosis, so despite initially negative findings in the endomyocardial biopsies the diagnosis of cardiac sarcoidosis seemed reasonably supported.

Figure 5.

Immunohistochemistry demonstrating (A) non-necrotising granuloma with two Langhans giant cells (Elastica-van-Gieson stain) and (B) epitheloid cells (H&E stain).

TREATMENT

In order to prevent a fatal arrhythmic event, an implantable cardioverter defibrillator (ICD) was inserted a few days after the initial MRI but before the final diagnosis was confirmed. At the time of discharge, the patient was treated with metoprolol; once the diagnosis of sarcoidosis was definite, an additional therapeutic regimen involving corticosteroids was initiated starting at 1 mg/kg body weight. A few days after the introduction of corticosteroid treatment, the patient experienced the first ICD discharge due to sustained ventricular tachycardia; 2 weeks later after an “electrical storm” with repeated inefficient ICD responses the patient was admitted to the intensive care unit. Ajmaline infusion initially helped to suppress further ventricular arrhythmias; soon thereafter focal ablation of arrhythmogenic foci failed due to initiation of complex electrical disturbances. Maintenance of sinus rhythm was finally achieved with amiodarone loading. During the next few months the patient experienced additional episodes of cardiac arrhythmia resulting in either antitachycardia pacing or ICD discharges. Amiodarone treatment was escalated from 200 to 300 mg/day; when a stable condition as regards arrhythmias had been reached, corticosteroids were titrated down to a maintenance dosage of 15 mg/day over a period of several months. For left ventricular dysfunction and in order to elevate potassium levels, the patient received the aldosterone inhibitor eplerenone; long-term treatment with ACE inhibitors could not be tolerated due to symptomatic hypotension. Furthermore, vitamin D and calcium supplementation were given as osteoporosis prophylaxis.

OUTCOME AND FOLLOW-UP

The overall clinical status of our patient, especially regarding signs and symptoms of left ventricular dysfunction, remained stable. Repeated echocardiography demonstrated near normal left ventricular function (EF 50–55%) despite slightly elevated NT-pro-BNP-levels (723 pg/ml, reference range <125 pg/ml). Regular non-invasive investigation including echocardiography, laboratory tests and evaluation of pulmonary function, did not indicate progression of systemic disease; a decrease in thickening of the interventricular septum from 19 to 13 mm within 9 months as displayed by echocardiography suggested regression of myocardial infiltration following therapy with steroids. Owing to the necessary implantation of an ICD, additional MRI scans could not be performed in our patient. As there are no appropriate guidelines regarding pharmacological treatment, the duration of corticosteroid application and maintenance dose remain empirical. As the patient tolerated the steroid treatment reasonably well, we chose to slowly taper doses to 15 mg/day where they have remained for several months. In order to non-invasively identify subclinical relapse of sarcoidosis quickly, we plan to use FDG-PET to monitor disease activity and response to treatment in the future.

DISCUSSION

A number of case reports refer to cardiac sarcoidosis; however, the case report presented here identifies several important aspects of the disease. The difficulty finding the correct diagnosis of cardiac sarcoidosis is mirrored in various necropsy reports demonstrating a high prevalence of subclinical and unsuspected cardiac histological involvement.^1,9 In a recently published case report, arrhythmogenic right ventricular cardiomyopathy concealed cardiac sarcoidosis, with the correct diagnosis only revealed by histological analysis of the patient’s heart after transplantation.¹⁰ Currently, the only available guidelines for diagnosing cardiac sarcoidosis have been published by the Japanese Ministry of Health and Welfare. These diagnostic criteria state that the gold standard is histologically confirmed evidence of cardiac sarcoidosis rather than clinically based evidence. In the latter case, electrographic, morphological and/or functional scintigraphic or haemodynamic abnormalities have to be accompanied by extra-cardiac histological evidence for granulomatous disease.¹¹ These guidelines have been applied in numerous studies for the diagnosis of cardiac sarcoidosis; however, their significance has never been prospectively validated. The present case once more demonstrates the difficulties of successful endomyocardial biopsies. Biopsies are routinely taken from the right ventricular apical septum, while the areas mostly affected are the basal and lateral free left ventricular wall. Furthermore, the patchy distribution of sarcoid granulomas in the myocardium accounts for the low sensitivity of endomyocardial biopsies, which has been described to be only around 50%.¹²

In patients with known systemic sarcoidosis, electrocardiography and echocardiography are useful methods for evaluation of heart function and may indicate cardiac involvement; however, these methods are not adequate for detecting microscopic myocardial involvement in sarcoidosis.¹³ Other imaging techniques such as radionuclide techniques, gallium-67 scintigraphy, PET scan or MRI are more appropriate for diagnosing myocardial involvement in sarcoidosis. The superior anatomical resolution of MRI in combination with late-phase gadolinium contrast enhancement enables the detection of very small amounts of fibrous replacement scar tissue where the contrast dye accumulates while it is washed out of healthy myocardium.¹⁴ This technique displays excellent agreement with histopathological findings in patients with cardiac sarcoidosis.¹⁵ Similar resolution in early contrast enhanced MRI has been observed in patients with myocardial inflammation as a result of active cardiac sarcoidosis under anti-inflammatory therapy.¹⁶ In addition, areas of high signal intensity on T2-weighted contrast MR images have been shown to be consistent with myocardial oedema in patients with cardiac sarcoidosis.¹⁷ The main drawback of the method is that patients with implanted pacemakers and/or ICD are unable to take advantage of it, as in our patient’s case. 18F-FDG has been observed to be accumulated by inflammatory cells; myocardial uptake of the tracer has also been proven by PET scan.¹⁸ 18F-FDG-PET has demonstrated higher sensitivity for the detection of myocardial involvement than other radionuclide examinations such as 67-Ga- or Tc-MIBI-scinigraphy¹⁹; however, the specificity of PET is relatively poor compared to contrast enhanced MRI. A recently published case report has demonstrated the utility of PET scan in managing steroid dose by identifying a granulomatous stage with accumulation of active inflammatory cells in the myocardium.²⁰

Arrhythmias are a common feature of myocardial sarcoidosis. Complete heart block is one of the most common findings,²¹ while ventricular tachycardia has often been described as the primary presentation of sarcoidosis.^22–24 Sarcoid granulomas in the myocardium easily become foci for abnormal automaticity, increasing the occurrence of re-entrant tachyarrhythmia. Papillary muscle involvement resulting in mitral regurgitation²⁵ and cardiac tamponade due to pericardial effusion²⁶ are rare cardiac manifestations. These conditions often require implantation of pacemakers and defibrillators; programmed ventricular stimulation may help identify patients at high risk for future arrhythmic events.²⁷ Importantly, initiation of anti-inflammatory therapy is not necessarily associated with decreased arrhythmic events;^28–30 this phenomenon might be explained by increased electrical instability due to alterations in the microstructure of the myocardium.

Corticosteroids are clearly indicated in cardiac or neurological disease, while the use of systemic steroids in pulmonary disease is not as clear cut. Although there are currently no guidelines concerning the initial dosage of steroids for cardiac disease, higher starting doses of 60–80 mg for the first 6–8 weeks or alternatively 1 mg/kg body weight have been recommended by various societies.³¹ Additional immunosuppressive therapies using methotrexate, cyclophosphamide or cyclosporine have also been introduced in the treatment of cardiac sarcoidosis.³ While these agents seem to be of value in selected patients, they lack a proven survival benefit as do corticosteroids. Recently, a case of cardiac sarcoidosis presenting with atrio-ventricular block and extensive systemic disease manifestations has been described. Monotherapy with infliximab led to rapid resolution of pulmonary infiltrations and consistently good cardiac performance with no dependency on the initially implanted three-chamber pacemaker.³² Finally, cardiac transplantation remains an option for some patients with severe unresponsive heart failure secondary to extensive sarcoid infiltration.³³ Recurrence of the disease in the donor organ has been described in a few cases.³⁴

In summary, the described case displays several features typical of cardiac sarcoidosis as follows: manifestation of the disease with a non-sustained ventricular tachycardia, difficulties in securing tissue diagnosis, complicated follow-up due to lacking inflammatory markers, inability to repeat cardiac MRI and ongoing ventricular arrhythmias.

LEARNING POINTS

• Cardiac sarcoidosis should be considered in cases of otherwise unexplained rhythm disturbances such as ventricular tachycardia or heart block.

• The diagnosis of cardiac sarcoidosis requires histological confirmation using either cardiac or extracardiac tissue; in the latter case, non-invasive diagnostic tools are also needed.

• Contrast-enhanced MRI is an excellent imaging technique to evaluate cardiac function and characterise myocardial tissue.

• Corticosteroid therapy is indicated for cardiac sarcoidosis; immunosuppressive agents may be used for refractory cases or in patients intolerant of steroid therapy.

• Ventricular arrhythmias complicating cardiac sarcoidosis often demand multiple anti-arrhythmic strategies, including implantable cardioverter defibrillators as potentially life-saving devices in a population at high risk of sudden death.