T1 mapping in myocarditis – headway to a new era for cardiovascular magnetic resonance

Abstract

Myocarditis is a major cause of cardiac morbidity and mortality, particularly in young patients. A spectrum of challenges besets this condition, from establishing the diagnosis to effective treatment. Endomyocardial biopsy remains the diagnostic gold standard, despite its invasiveness, low diagnostic yield and a paucity of consequential management pathways. Cardiac magnetic resonance by Lake Louise criteria has contested to become the non-invasive diagnostic alternative by providing confirmation of disease. The advent of T1 mapping now allows a high diagnostic accuracy in confirmation and exclusion of disease, discrimination of stages and activity of disease. Alongside the research into the mechanisms and potential therapeutic targets, cardiac magnetic resonance confidently claims a prime role within a modern diagnostic pathway in clinically stable patients with suspected myocarditis.

Keywords:

• Lake Louise criteria
• myocardial inflammation
• myocarditis
• T1 mapping

Myocarditis is an autoimmune inflammation of myocardial tissue triggered by an external cause, most commonly by viral infection [1,2]. In an important minority of patients, it leads to significant morbidity and mortality, especially of the young; myocarditis is accountable as the underlying cause of sudden cardiac death in 2–42% of cases, as well as for 9–16% of adults and 46% of children’s unexplained non-ischemic dilated cardiomyopathy. One-third of patients with evidence of viral particles on myocardial histology progresses to heart failure with 50% mortality within 2 years. Outcome and prognosis depend on etiology, clinical presentation and disease stage. Due to heterogeneous clinical presentations with commonly nonspecific symptoms and absence of an easy to use and widely available diagnostic test, delaying recognition of disease, the true incidence of myocarditis is difficult to determine and probably underestimated [3]. Nowadays, the finding of raised troponin levels channels these patients along the diagnostic pathway of acute coronary syndromes, whereby the finding of unobstructed coronary arteries provides the clinical suspicion as well as demands confirmation of disease [4].

Current expert consensus of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases supports the use of endomyocardial biopsy (EMB) as the gold standard for the diagnosis of definitive myocarditis [1], based on the evidence of providing the benefit in steroid-responsive conditions such as giant cell myocarditis (GCM), the confirmation of which requires EMB. However, a combination of the relatively low incidence of GCM, a limited availability of EMB expertise, its procedural risks and commonly low diagnostic yield are responsible that this diagnostic strategy is widely perceived as impractical in most cases of suspected myocarditis, and only performed for the fulminant presentations with hemodynamic compromise, as set out by the American and European guidelines [3]. The comparative effectiveness of EMB in differentiating between active and chronic stages in clinical scenarios, or in guiding treatment in steroid-responsive conditions such as GCM has not been assessed against the more prevalent biopsy-naïve clinical management in a controlled scenario [1–3,5].

In routine practice, a non-invasive pathway is clearly preferable for establishing the diagnosis and guiding clinical management decisions. Cardiac magnetic resonance (CMR) is gaining a principal role in establishing the diagnosis in clinically stable patients and adding essential information to the work-up of patients with raised troponin levels and finding of unobstructed coronary arteries [4,6]. Evidence from EMB-proven cases of active and chronic myocarditis revealed increased signal intensity on T2 and typical patterns of late gadolinium enhancement (LGE) imaging as diagnostic criteria in CMR. These imaging findings correspond to edema as a sign of an inflammatory process and necrosis/scar and provide the basis of Lake Louise criteria for the recognition of myocarditis by CMR [6]. Originally a part of the criteria, the global gadolinium enhancement ratio based on T1 imaging was subsequently shown to provide no additional diagnostic benefit [7]. The presence of LGE has been shown to bear prognostic relevance and poor outcome [8]. The strength of Lake Louise criteria is in allowing confirmation of disease when findings are present, whereas in their absence, the diagnosis can remain unclear despite a convincing clinical picture. The lack of sensitivity can be explained by the different histological forms of myocardial inflammation, which can occur in myocarditis [9]. These include the more regionalized, infarct-like presentation with prevalent cell necrosis and interstitial edema, as well as the diffuse cardiomyopathic and arrhythmic presentations, where cell apoptosis and intracellular edema predominate, substantiating the differential ability of LGE imaging to visualize these pathophysiological substrates. LGE is present when the process is sufficiently extracellular as well as regionalized, allowing the development of an imaging contrast between highly affected tissue areas, which accumulate the contrast agent, and less affected areas, which are used for comparison [10]. Abundant interstitial edema also leads to magnetization transfer from extracellular gadolinium to intracellular water, further increasing the observed signal [11]. On the contrary, intracellular processes compress the extracellular space reducing the space for gadolinium accumulation to small and evenly distributed quantities with little regional difference [9,10] leading to a normal LGE image. Another diagnostic challenge is occurring, when the first CMR study is performed in the chronic stage of the disease [6], and where the predominating signs of functional impairment and non-ischemic LGE patterns, such as midwall stria, may be more readily underpinning the diagnosis of dilated cardiomyopathy [12]. A possible persistent low-grade myocardial inflammation is neither visualized with T2 imaging nor picked up by LGE, which will only reveal the presence of residual and regional cell death [13,14].

Novel quantitative tissue characterization techniques offer promise to overcome some of the above limitations of the Lake Louise criteria. T1 mapping, a novel technique for quantitative tissue characterization, allows an assessment of intracellular and diffuse involvement, as well as provides the ability to discriminate between different stages and severity of the myocardial inflammation [15]. Native myocardial T1 measurements are highly sensitive in detecting myocardial inflammation over and above T2 weighted imaging in clinical studies with acute myocarditis as well as acute myocardial infarction [15–17]. Furthermore, a recent study by our group provides the evidence of the ability of native T1 to capture diffuse myocardial involvement, as well as provides a novel diagnostic algorithm to discriminate acute and convalescent stages based on the complementary ability of native T1 and LGE in detecting diffuse and regional myocardial involvement, respectively [15]. The novel diagnostic algorithm provides an easy to implement imaging protocol that captures intracellular, interstitial and regional disease by complementing the readouts of native T1 imaging and/or LGE, as appropriate, to approximate the pathophysiological complexity during the different stages in patients’ myocarditis [15]. We found that an increase in native T1 values of 5 standard deviations (SD) or more above the mean of the normal range [18] unequivocally confirms the acute stage of disease, even in the absence of any LGE. Convalescent stages of disease are either defined by quiescent readouts (normal native T1 and absence of LGE or areas of irreversible injury by LGE), or by a degree of persistent inflammation (native T1 within 2–5SD above the normal range [18], presence or absence of LGE). Such complementary approach not only provides high diagnostic accuracy in confirmation of disease but also a high negative predictive value and exclusion of disease, as confirmed in a prospective study cohort [18]. Thus, a novel algorithm, which uniquely unites the strengths of the above imaging techniques to detect diffuse and regional disease, as well as ability to stage and grade myocardial inflammation, by differentiating between acute and active inflammatory processes, and chronic or convalescent stages of myocarditis, respectively, heralds an important upgrade of the original Lake Louise criteria [6,19,20]. Accordingly, other groups have also confirmed the superiority of T1 mapping techniques improving the diagnostic performance of CMR in acute myocarditis compared to conventional ‘two of three’ Lake Louise criteria adding native T1 or extracellular volume fraction to LGE imaging [21,22]. For the time being, particular setups of available T1 mapping methods are site and vendor specific, and accuracy and precision of T1 measurements may vary between CMR systems, sequences and post-processing approaches; therefore, each center need to establish their own local normal ranges before their application into clinical routine.

T2 mapping also holds promise to detect acute inflammation with the potential to address conventional T2-weighted limitations. Myocardial T2 values are increased in acute inflammatory conditions and may help to distinguish between active and chronic stages of myocarditis [23–25]. T2 values changed proportionally to T1s in a model of ischemia–reperfusion validated against microspheres, in a way that was consistent with the presence of myocardial edema [26]. Further evidence might reveal which mapping technique yields higher diagnostic accuracy in different scenarios.

In summary, the advent of T1 mapping and complementation with LGE imaging further strengthens the position of CMR as the comprehensive and accurate diagnostic tool in patients with suspected myocarditis, by allowing confirmation or exclusion myocardial inflammation and as well as assess the activity and severity of disease.

In addition to challenging recognition of the disease, the care management options in myocarditis remain obscure. It is unknown, whether establishing an early diagnosis in clinically stable patients improves the clinical course or facilitates treatment. Active research and controlled clinical trials are underway, which particularly focus on the mechanisms and potential therapeutic targets. The concerns about safety of immunosuppressive therapy in early disease, based on equivocal results from animal studies, require further investigation [1,2]. Neutralization or immunoadsorption of serum cardiac autoantibodies has suggested improvement in left ventricular function and reduction of myocardial inflammation but these results must be confirmed in controlled clinical trial [27,28]. CMR can confidently claim its prime role in supporting a modern diagnostic pathway in clinically stable patients. CMR by novel mapping techniques offers a quantifiable measure of acute injury and chronic damage, which may be applied to identify the most appropriate stage for treatment opportunity. T1 mapping may thus offer a novel approach to detect and grade myocardial inflammation and monitor disease progression or regression. Hypothetically, T1 mapping might be applied to monitor myocardial behavior after one or another therapeutic strategy. Further studies will be required to examine these questions and clarify whether and what treatment might reduce the severity of changes observed as a chronic sequel of the viral myocarditis.

Financial and competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.