Positron emission tomography in clinically suspected myocarditis – STREAM study design
Introduction
Myocarditis is an inflammatory disease of the myocardium with heterogeneous aetiology (viral, bacterial and fungal infections, systemic diseases, autoimmune dysregulation, drugs and toxins) [1]. It usually affects young or middle-aged people, generating serious social problems, though diagnosis and risk stratification are still challenging. For the majority of people, myocarditis may be asymptomatic or cause mild self-limiting symptoms, but in some patients the disease is unpredictable, leading to life-threatening arrhythmias, heart failure (HF), cardiogenic shock or sudden death [[1], [2], [3]]. After the acute phase, some patients develop dilated cardiomyopathy (DCM) with clinical signs and symptoms of HF with or without ongoing viral infection and/or inflammation in the myocardium [2]. Despite the fact that in approximately 50% of cases myocarditis may resolve itself spontaneously, some degree of fibrosis may be demonstrated by cardiac magnetic resonance (CMR) [[4], [5], [6]]. Therefore, patients require long-term, strict follow-up to detect deteriorating cardiac function.
According to the position statement of the European Society of Cardiology (ESC) Working Group on Myocardial and Pericardial Diseases, a uniform approach to the diagnosis of myocarditis with the use of non-invasive imaging modalities (echocardiography (Echo), CMR) is recommended, as well as confirmation of ongoing myocarditis via endomyocardial biopsy (EMB), using histopathology, immunochemistry and a polymerase chain reaction (PCR) for the virus genome [2,7,8]. EMB is a gold standard, but it is still not a routine practice, even in tertiary care centers, due to the lack of experienced medical staff and adequate facilities, as well as the risk of complications. CMR is the imaging reference for diagnosis of myocarditis based on the Lake Louise criteria (LLC) (characterization of the inflamed myocardium by identifying oedema, as well as early and late gadolinium enhancement (EGE and LGE, respectively)) [2,9]. However, as with the Dallas criteria for EMB, it is now clear that the LLC also have major limitations [10]. Diagnostic accuracy of the LLC in identifying acute myocarditis has been estimated at 83%, with 67–80% sensitivity and 87–91% specificity [6,11]. Therefore, new emerging CMR techniques are under intense research (T1- and T2-tissue mapping) [11,12]. Baccouche et al. revealed a strong correlation between CMR and EMB in troponin-positive patients but the correlation was worse in patients with a longer history of symptoms [13]. CMR does not allow the ruling out of myocarditis, thus it should not be considered the gold standard [10].
The 2013 ESC recommendations did not support nuclear imaging in the diagnosis of myocarditis due to insufficient evidence [1], but there is now a promising non-invasive method, i.e. 18F-2-fluoro-2-deoxy-d-glucose positron emission tomography/computed tomography (FDG-PET/CT) which could be useful in the diagnosis of myocarditis. FDG-PET/CT provides metabolic information about increased myocardial FDG uptake in inflamed myocardial tissue. FDG-PET might be particularly useful in suspected chronic myocarditis, where CMR accuracy is low. In a small study of patients with DCM, FDG-PET/CT showed a strong correlation with the diagnosis of myocarditis and was presented as a very promising diagnostic method [14]. FDG-PET imaging already has an established role in the detection of cardiac and extracardiac localizations of sarcoidosis and therapy monitoring [15]. An additional advantage of FDG-PET/CT is that it can be performed on patients with e.g. implantable cardiac devices, where CMR cannot be carried out.
The combination of EMB with non-invasive techniques (CMR, FDG-PET/CT) might allow considerable improvement in diagnostic sensitivity. In this setting, FDG-PET/CT imaging could provide additional information about ongoing myocardial inflammation and may be helpful in determining the appropriate duration of exercise restriction and the prescription of cardio-protective treatment. Current data on the role of FDG-PET in myocarditis is limited but it has been shown that this modality may be useful in detecting and localizing the active inflammatory process, which may be particularly useful in patients from the “grey zone”. Well-designed studies are needed to confirm the preliminary findings and to assess the value of FDG-PET/CT for clinical management and risk stratification in patients with clinically suspected myocarditis.
Section snippets
Study design
The STREAM (Evaluation of the feaSibility of 18F-fluoro-deoxy-glucose positron emission Tomography/computed tomography imaging comparing to cardiac magnetic Resonance and Endomyocardial biopsy findings in clinicAlly suspected Myocarditis) study is a prospective, observational, multicentre cohort study. The study is registered on ClinicalTrials.gov (NCT04085718). The study is approved by the Research Ethics Committee and will be conducted within the principles of Good Clinical Practice and in
Discussion
The diagnosis of myocarditis still requires significant improvement. CMR is a gold standard for non-invasive diagnosis of clinically suspected myocarditis, but with limited sensitivity and specificity. The currently available data, although scarce, suggest that FDG-PET/CT alone or in combination with CMR may be a useful tool for improving the diagnosis of myocarditis. The current study will provide clinical data on the feasibility of FDG-PET/CT imaging alone or in combination with CMR (EMB as a
Limitations
There are limitations related to the study design that we would like to mention. Firstly, the sample size of subjects is relatively small, though this study was designed as a pilot study. Secondly, patients only undergo RV EMB. There is some data indicating that biventricular (RV and LV) EMB increases the diagnostic potential of the method. To increase the diagnostic accuracy, more myocardial tissue samples (6–10) are taken. Thirdly, a number of physiological and pathological factors increase
Authors' contributions
KO, AT, MK, ALPC, GO, MG designed the trial (investigator-initiated study). KO and AT obtained funding for the trial. KO, AT, MK, ALPC, RM, MG will participate in data collection. KO, AT, DSS, VM and MK drafted the manuscript. ALPC, DŠŠ, ADR, PMS, RM, RM, LK, MG, GO provided critical revision of the manuscript. All authors read and approved the final manuscript. All authors participated in the study and will be included in the publications resulting from the study.
Authors' information
KO and ADR are PhD medical doctors performing the endomyocardial biopsy procedure. AT is a PhD medical doctor performing echocardiographic examinations. MK is a PhD medical doctor performing and assessing FDG-PET/CT and SPECT examinations. ALPC is a professor, a former working group executive and the first author of the ESC position paper on myocarditis. RM is a senior staff physician and a specialist in Hematology, Cardiology and Clinical Immunology. RM is a medical doctor performing and
Collection and availability of data and materials
The investigator must maintain source documents for each patient in the study, consisting of visit notes, hospital or clinic medical records containing demographic and medical information, laboratory data, and the results of any other tests or assessments. Data will by entered by investigators into a secured database. Patient privacy will be ensured by using patient identification code numbers.
The study investigators have full access to the study datasets. External requests for study data will
Funding
The study is financed from statutory funds of the Medical University of Warsaw and two research grants (KO received the “Young Researcher Grant” from “Club 30” of the Polish Cardiac Society and AT received a Scientific Grant from the Polish Cardiac Society unconditionally founded by Servier) – an investigator-initiated study. The project is investigator initiated and there is no influence of third parties on the study design, data collection or interpretation of data.
Ethical approval
All procedures in the study involving human participants will be performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. In the event of changes to the research protocol, they will be reported to the bioethics committee.
Informed consent
Informed consent will be obtained from all individual participants included in the study.
Declaration of Competing Interest
AT, KO, MK, ALPC, DSS, ADR, RM, PMS, RM, LK, GO, MG declare no conflict of interest.
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