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Long-Term Evolution and Prognostic Stratification of Biopsy-Proven Active Myocarditis

Myocarditis is an inflammatory disease of the myocardium, diagnosed by established histological, immunological, and immunohistochemical criteria. The disease usually has an heterogenous presentation (heart failure, arrhythmias, chest pain, or a combination of these elements). The diagnosis is often challenging and the long-term prognosis is still under investigation. Limited data are also available for the prognostic stratification. With the aim of investigating the natural history of patients with active myocarditis diagnosed by endomyocardial biopsy (EMB) and early predictors of long-term prognosis, a well known Italian group guided by prof. Sinagra from Trieste has recently published its prospective study on 82 patients with biopsy-proven active myocarditis (1).

From 1981 to 2009, 82 patients with EMB-proven AM were consecutively enrolled in the Trieste Heart Muscle Disease Registry. Diagnosis of AM was made in accordance with Dallas Criteria; cases with borderline myocarditis were excluded from the study. After 1992, the diagnosis of AM was established when immunohistochemical analysis detected a myocardial immune activation in addition to positivity of the Dallas Criteria. All patients (except one, who refused the examination) were followed with a scheduled reevaluation at 6 (3–9) months from baseline in the HF Outpatient Clinic. The study outcome measure was long-term heart transplantation (HTx)–free survival.
Patients were categorized in 3 groups according to the main pattern of disease onset:
Group 1. HF: NYHA II to IV, LVEF<50%.

Group 2. Arrhythmias: electrocardiographic evidence of bradyarrhythmias or tachyarrhythmias.
Group 3. Chest pain.
Furthermore, the study population was categorized at the 6-month follow-up according to an improvement/normality criterion, defined as LVEF increase >20 percentage points or LVEF≥50%. The end of follow-up was considered as December 31, 2012 (last check date of status for alive patients) or the date of death or HTx.

Main Results:
Patients were young (age 38±16 years) and predominantly males. The interval between the onset of cardiac symptoms and hospitalization was shorter than 1 month in 75% of patients. On EMB, 75 patients (91%) had lymphocytic myocarditis. The interval between the onset of cardiac symptoms and hospitalization was significantly longer in patients with HF in comparison with the other groups; however, it was shorter than 2 months in 75% of HF patients. Among patients with arrhythmic onset, 10 presented with tachyarrhythmias (6 with ventricular fibrillation/flutter or sustained ventricular tachycardia; 1 with frequent symptomatic ventricular premature beats; 3 with supraventricular arrhythmias) and 10 presented with bradyarrhythmias (2 with second-degree atrioventricular block and 8 with third-degree atrioventricular block).
At 6 months, 41 subjects (53%) satisfied the LVEF improvement/normality criterion. During a mean follow-up of 147±107 (median, 140; first-third quartile, 54–222) months, 23 (28%) patients died, and 7 (9%) patients underwent HTx. HF was the most prevalent cause of death (14; 61%), followed by sudden cardiac death (3; 13%), and noncardiovascular death (3; 13%). For 3 (13%) patients, the cause of death remained unknown. Long-term HTx-free survival was significantly different among groups according to the pattern of disease onset, with the poorest outcome for HF patients.
At multivariable analysis, the independent predictors of long-term HTx-free survival were the left atrium enlargement and the presence of LV systolic dysfunction at enrollment.
The short-term reevaluation presented additional incremental predictive value in comparison with the baseline evaluation, patients experiencing an increase of LVEF by 20 percentage points or a LVEF≥50% and a low NYHA functional class at 6 months demonstrated an excellent long- term prognosis.

Clinical Implications and Study Limitations:
The relatively limited number of cases suggests that myocarditis is often unrecognized and underdiagnosed. EMB remains the main tool to diagnose acute myocarditis, although it may present accuracy limits (number and sites of bioptic samples, proper timing of the procedure, and histopathological interpretation). Consequently, the real incidence of suspected acute myocarditis without criteria for EMB remains uncertain. Patients with preserved LVEF at disease onset presented a good long-term prognosis. Prognosis was related to initial presentation with the worse outcome in those presenting with heart failure, depressed LVEF or not improving LVEF and the better in those presentating with chest pain (invariably characterized by preserved LVEF and excellent prognosis in the long-term follow-up). An intermediate prognosis was detected in those with arrhythmic presentation.


In conclusion LV dysfunction at baseline identifies patients characterized by poorer long-term prognosis. 6 months clinical/instrumental reevaluation may provide an incremental risk stratification: early improvement/normality of LVEF was independently associated with a favorable long-term out- come.
Main study limitations are related to the limited sample size, the possible selection  bias for patients that were enrolled in a tertiary referral center for cardiomyopathies and HF, the long enrollment time over 28 years with potential significant changes in diagnostic and therapeutic approaches to myocarditis.
Additional multicenter studies and/or registries with larger samples and long term follow-up are needed to confirm the study findings. A recently published position paper of the WG on myocardial and pericardial diseases (2) has recently reviewed the current knowledge on clinical presentation, diagnosis and treatment of myocarditis, and proposed new diagnostic criteria for clinically suspected myocarditis and its distinct biopsy-proven pathogenetic forms with the aim to bridge the gap between clinical and tissue-based diagnosis, to improve management and provide a common reference point for future research on the topic.


1. Anzini M, Merlo M, Sabbadini G, Barbati G, Finocchiaro G, Pinamonti B, Salvi A, Perkan A, Di Lenarda A, Bussani R, Bartunek J, Sinagra G. Long-term evolution and prognostic stratification of biopsy-proven active myocarditis. Circulation 2013 Nov 26;128:2384-94.

2. Caforio AL, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J,Felix SB, Fu M, Heliö T, Heymans S, Jahns R, Klingel K, Linhart A, Maisch B, McKenna W, Mogensen J, Pinto YM, Ristic A, Schultheiss HP, Seggewiss H, Tavazzi L, Thiene G, Yilmaz A, Charron P, Elliott PM; European Society of Cardiology Working Group on  Myocardial and Pericardial Diseases. Current state of knowledge on aetiology,diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34:2636-48.


Notes to editor

Presented by Massimo Imazio, MD, FESC- Cardiology Dpt. Maria Vittoria Hospital, Torino. Italy.

Marco Anzini, MD; Marco Merlo, MD; Gastone Sabbadini, MD; Giulia Barbati, PhD; Gherardo Finocchiaro, MD; Bruno Pinamonti, MD; Alessandro Salvi, MD; Andrea Perkan, MD; Andrea Di Lenarda, MD; Rossana Bussani, MD;
Jozef Bartunek, MD, PhD; Gianfranco Sinagra, MD, FESC

From the Cardiovascular Department, “Ospedali Riuniti di Trieste” and University of Trieste, Trieste, Italy
The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.