Methods
Patient Population
We included 153 patients referred to our centre with atrial arrhythmias for evaluation in the period between January 2015 and July 2018. We excluded patients with structural heart disease, post-operative AF, critically illness, significant dyselectrolytemias and patients with conventional risk factors for AF.9 We also excluded patients with ventricular arrhythmias. There were 45 patients without an underlying cause for AF. We evaluated these 45 patients for evidence of atrial inflammation. 18F FDG PET demonstrated atrial uptake in 24 patients. Biopsy evidence of myocarditis was found in 15 out of these 24 patients. Atrial tachyarrhythmias with evidence of atrial inflammation and mediastinal lymphadenopathy was observed in 15 patients (30%). In this study, we describe the clinical features of these patients presenting with atrial arrhythmias with evidence of inflammation on imaging and biopsy.
We evaluated the patient charts and reports for information on past illness, procedures, and therapies. Informed consent was obtained from all patients.
Diagnostic Evaluation
Detailed history and clinical examination were performed in all patients. Laboratory tests for complete blood counts (CBC), erythrocyte sedimentation rate (ESR), hs-CRP, Renal function, Liver function, Thyroid function and electrolytes were performed in all patients. Coronary artery disease was ruled out by stress testing and coronary angiography when indicated. A 12-lead electrocardiogram at baseline and during the tachyarrhythmia was evaluated in all patients. The diagnostic evaluation protocol that was used has been summarized in the Figure 2. The following imaging modalities were also used in all patients:
  1. Echocardiography – A detailed echocardiogram was conducted for biventricular function, regional wall motion and valve dysfunction. We also measured the left atrial (LA), right atrial (RA) volumes and the left ventricular ejection fraction (LVEF). The American society of Echocardiography (ASE) recommendations for chamber quantification were used for these measurements.10 We used the 2012 WHF echocardiographic criteria for rheumatic heart disease to rule out rheumatic heart disease. We also ruled out acute rheumatic fever with the modified Jones criteria.11
  2. Delayed gadolinium enhancement Cardiac Magnetic resonance (DE-CMR) – A CMR was performed for ventricular function and delayed enhancement in the ventricular myocardium in 6 of these patients.
  3. Positron Emission tomography (18 FDG PET-CT) - Was performed in all the patients according to standard protocols with a 16-slice scanner (Siemens). The 18F-FDG PET/CT images was obtained with patients on a high fat, low carbohydrate diet for 24 hrs with an overnight fast of 12 – 16 hours prior to the imaging. The images were interpreted visually for evidence of uptake in the atrial or ventricular myocardium. We recorded the site of uptake in the atria and classified it according to the following regions: 1. Right atrial appendage (RAA) 2. Right atrial free wall (RA) 3. Interatrial septum (IAS) 4. Left atrial appendage (LAA) 5. Left atrial anterior wall (LAAW) and left atrial posterior wall (LAPW)
  4. Computerized tomography and Magnetic resonance imaging of the brain was performed in patients presenting with stroke.
  5. Evaluation of aetiology – A detailed physical examination for evidence of rheumatic fever, sarcoidosis, and tuberculosis. A previous history of tuberculosis was also sought. A tuberculin skin test was performed in all patients with 5 tuberculin units of purified protein derivative. An induration of greater than 10 mm at 48 hours was interpreted as a positive test. An endomyocardial biopsy was performed in 1 patient and a biopsy of enlarged lymph nodes was performed in all the patients. The biopsy specimens were evaluated by histopathology with Gram’s staining and haematoxylin and eosin staining. Staining and cultures for mycobacterium and fungi were performed in all the biopsy specimens. A polymerase chain reaction for tuberculosis was performed in all the patients on tissue biopsy specimens. The diagnosis of Cardiac Sarcoidosis was according to the Expert Consensus Recommendation Criteria by Birnie et. al.12 The diagnosis of Cardiac sarcoidosis was based on Histopathological or clinical criteria and confirmed as definite with a histological diagnosis from myocardial tissue or probable based on clinical criteria and extracardiac biopsy diagnosis.
Management
Antiarrhythmic therapy
Initially all patients were treated with rate control medications such as beta blockers, digoxin, and calcium channel antagonists. The rhythm control medications used were sotalol, flecainide and amiodarone. Oral anticoagulation was recommended in all patients with evidence of myocarditis.
Electrophysiology study and Radiofrequency ablation
An EPS with ablation of atrial flutter was performed in 4 patients who continued to have arrhythmias despite AADs. The ablation was performed with three-dimensional mapping system (CARTO, Biosense Webster), a Stockert radiofrequency generator (Stockert GmBh, Freiburg, Germany) and an 8-F irrigated tip ablation catheter. The success of atrial flutter ablation was defined as bidirectional block and AVNRT ablation was defined as non-inducibility.
Management of underlying disease
Therapy of myocarditis in the form of either sarcoidosis or tuberculosis was added to the management of patients after appropriate diagnosis. The management protocol used is highlighted in Figure. Patients were treated with oral corticosteroids (prednisolone 0.5mg/kg/day to a maximum dose of 60 mg/day) for 8 weeks initially. Patients were evaluated at every follow up visit by clinical evaluation, ECG, echocardiography, and18FDG-PET scans. After 8 weeks, the corticosteroids were tapered, and oral methotrexate started concurrently at a dose of 7.5 mg/week. Methotrexate was continued for 2 years. The duration and titration of therapy was guided by disease response. The response was assessed by 18F-FDG-PETs and clinical evaluation. After the initial phase, patients were followed up at 3- 6 monthly intervals. In patients with evidence of tuberculosis, anti-tuberculosis therapy was instituted according to standard recommendations.
Statistical Methods
Continuous variables were represented as mean and standard deviation where data follows the normal distribution, otherwise as a median with range. Categorical variables were represented as frequencies and percentages. The paired t test was used to show the effect of treatment on LA, RA dimensions, LVEF and inflammatory parameters.