Chronic Active Myocarditis and Inflammatory Cardiomyopathy　― Challenges in Diagnosis and Treatment ―

Abstract

Myocarditis is a heterogeneous disease with diverse etiologies and clinical trajectories. Traditionally, its diagnosis has been guided by the Dallas criteria, which focus on histopathological features. Clinically, myocarditis is categorized as acute or chronic based on the duration since symptom onset. However, recent expert consensus, particularly in Western countries, has redefined myocarditis as either acute myocarditis or chronic inflammatory cardiomyopathy, including inflammatory dilated cardiomyopathy, reflecting advancements in viral genome analysis and histopathology. In 2023, the Japanese Circulation Society proposed the concept of chronic active myocarditis, a high-risk phenotype characterized by persistent inflammation and ongoing cardiomyocyte injury. The transition from acute myocarditis to its chronic phase involves complex immune mechanisms, with sustained myocardial inflammation driving ventricular remodeling and progression to heart failure. Cardiac magnetic resonance imaging and endomyocardial biopsy remain pivotal diagnostic modalities, though their diagnostic yield varies according to disease phase. Management strategies focus on heart failure treatment, arrhythmia control, and, in select cases, immunosuppressive therapy, particularly for virus-negative inflammatory cardiomyopathy. Although antiviral therapy has shown promise, its clinical efficacy remains uncertain. Given the evolving understanding of the chronic phase of myocarditis, further research is warranted to refine the diagnostic criteria and optimize personalized therapeutic strategies. This review gives a comprehensive overview of the pathophysiology, classification, and management of chronic myocarditis, with an emphasis on emerging disease concepts and their clinical implications.

Among the cardiovascular diseases, myocarditis is a relatively uncommon, so large-scale clinical studies are limited in number, making it challenging to establish well-structured clinical guidelines. Traditionally, the diagnosis of myocarditis has been made using the Dallas criteria, which are based on the histopathological findings of endomyocardial biopsy (EMB). Clinically, myocarditis is further categorized into acute and chronic forms, with the distinction generally based on the time elapsed since the onset of symptoms, typically ranging from 1 to 3 months.^1–3 However, recent position statements and expert consensus documents from Western countries, including Europe and the USA, have shifted towards classifying myocarditis into acute myocarditis and chronic inflammatory cardiomyopathy, with a global decline in the use of the term “chronic myocarditis”.^4,5 This shift reflects an improved understanding of the etiology, pathophysiology, and clinical course of myocarditis, driven by advances such as viral genome analysis and histopathological studies. Furthermore, diagnostic workup has also markedly improved, particularly through enhanced highly sensitive troponin measurement, and imaging modalities such as cardiac magnetic resonance imaging (CMR), enabling more precise clinical diagnoses of myocarditis.^6–10

The Japanese Circulation Society (JCS) has recently published updated guidelines for the diagnosis and treatment of myocarditis and newly defined “chronic active myocarditis”, which is a high-risk phenotype of chronic inflammatory cardiomyopathy.¹¹ Here, we will provide a comprehensive overview of the pathophysiology, definition, and clinical management of the chronic phase of myocarditis including chronic active myocarditis and chronic inflammatory cardiomyopathy, emphasizing these evolving disease concepts.

Pathophysiology and Definitions

Myocarditis represents a heterogeneous group of disorders that arise from a combination of genetic predisposition and environmental factors such as viral or bacterial infections, exposure to drugs or toxins, vaccination, and activation of the immune system.^12–14 Pathologically, myocarditis is characterized by inflammatory cell infiltration and myocardial cell injury, including degeneration and necrosis of cardiomyocytes adjacent to infiltrating inflammatory cells.^2,15,16 The clinical spectrum of myocarditis is remarkably broad, ranging from asymptomatic presentations to fulminant forms. Acute myocarditis typically follows a distinct clinical course, beginning with an initial inflammatory phase lasting approximately 1–2 weeks. During this phase, cardiomyocyte necrosis, cytokine production, and immune system activation contribute to myocardial dysfunction. This inflammatory phase is subsequently followed by a reparative phase, during which the active immune response subsides, and the damaged myocardium is progressively replaced by fibrotic tissue.⁴ Although the majority of acute myocarditis cases resolve spontaneously, a subset progresses to persistent inflammatory activity during the chronic phase.¹³ This progression can lead to conditions such as chronic myocarditis or chronic inflammatory cardiomyopathy, which may encompass inflammatory dilated cardiomyopathy (DCM).^5,17 From a clinical perspective, myocarditis can be broadly classified into acute myocarditis and the chronic phase of myocarditis including chronic inflammatory cardiomyopathy and inflammatory DCM (iDCM) based on onset patterns and temporal progression.^5,11

Notably, iDCM is a subset of DCM characterized by persistent myocardial inflammation, which leads to ventricular remodeling, systolic dysfunction, and heart failure (HF).^11,17 Approximately 20% of patients with myocarditis are estimated to develop DCM within 1 year.¹⁸ However, the exact rate of progression remains uncertain, largely due to the challenges in diagnosing myocarditis and identifying its underlying causes.¹⁸ A Japanese multicenter retrospective study investigating inflammatory cell infiltration in DCM showed that slightly more than 30% of patients with DCM were categorized as inflammatory cardiomyopathy according to the European expert consensus.^4,19

The progression from acute myocarditis to iDCM involves complex interactions between the viral infection, autoimmune responses, and dysregulated immune mechanisms.¹⁷ The initial stage of iDCM is often triggered by viral myocarditis in which cardiotropic viruses, such as coxsackievirus B, and adenovirus, infect cardiac myocytes,^20,21 leading to direct cellular damage and activation of the innate immune system via toll-like receptor pathways.²² In susceptible individuals, viral infections can initiate maladaptive autoimmune responses, whereby myosin-heavy chain proteins act as autoantigens.^21,23,24 During acute myocarditis, CD4⁺ and CD8⁺ T cells infiltrate the myocardium, releasing cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-6.^25,26 These pro-inflammatory cytokines exacerbate cardiomyocyte injury and promote fibrosis. Persistent immune activation, even after viral clearance, is a hallmark of the transition from acute inflammation to chronic myocarditis.²⁷ In some cases, the acute immune response fails to resolve, leading to chronic myocarditis. Chronic inflammation in iDCM is characterized by continuous activation of macrophages, T cells, and fibroblasts, which all release inflammatory mediators, including IL-1β, TNF-α, and matrix metalloproteinases, that promote cardiac fibrosis and left ventricular (LV) remodeling.²⁸ Persistent low-level viral replication in the myocardium may also contribute to chronic inflammation and progressive cardiac dysfunction. Cytokines such as TNF-α, IL-1β, and IL-6 play central roles in the pathogenesis of iDCM.^26,29–32 TNF-α induces negative inotropic effects, promotes cardiomyocyte apoptosis, and enhances fibroblast activity, leading to fibrosis.^29–31 IL-6 contributes to increased cardiomyocyte stiffness through titin phosphorylation,²⁶ while IL-1β induces pyroptosis, an inflammatory form of cell death.³² These cytokines also activate endothelial cells, facilitating leukocyte infiltration and perpetuating the inflammatory cycle.^33–35 Cardiac fibrosis is a defining feature of iDCM,³⁶ resulting from excessive extracellular matrix deposition by activated fibroblasts.¹⁷

Diverging Concepts and Definitions Among the Guidelines

Historically, the definitions of the clinical entities in the chronic phase of myocarditis have lacked international standardization, leading to inconsistencies across the guidelines (Table 1). For example, the previous JCS guidelines defined chronic myocarditis as a condition with evidence of cardiomyocyte injury,¹ but recent expert consensus statements from Western countries have described chronic myocarditis primarily as a transitional state between acute myocarditis and chronic inflammatory cardiomyopathy, without evidence of cardiomyocyte injury.⁵ As a consequence, there has been a global shift toward categorizing myocarditis into acute myocarditis and chronic inflammatory cardiomyopathy, with decreased use of the term “chronic myocarditis”. Furthermore, regarding the temporal classification, the previous JCS guidelines set the boundary between acute and chronic phases at approximately 3 months,¹ whereas Western expert consensus has adopted a shorter timeframe of 30 days.⁵

Table 1.

Differences in the Definitions of the Chronic Phase of Myocarditis in the Guidelines/Statements/Expert Consensus

Phenotype	Japanese Circulation Society Guidelines (2009)1	European Society of Cardiology Position Statement (2013)4	Ammirati et al. Expert Consensus Document (2020)5	Japanese Circulation Society Guidelines (2023)11
Chronic active myocarditis	Not defined (conceptually included in chronic myocarditis)	Not defined	Not defined	• Myocarditis ≥30 days after onset • Histologically characterized by inflammatory cell infiltration (leukocytes in myocardial tissue ≥14/mm2 with CD3-positive T cells ≥7/mm2) • Cardiomyocyte injury (degeneration/necrosis accompanied by encroachment of inflammatory cells at the perimeter of cardiomyocytes)
Chronic inflammatory cardiomyopathy	Not defined	Not defined (conceptually included in chronic myocarditis as inflammatory cardiomyopathy)	Myocardial inflammation persisting for ≥30 days after onset
			• Decreased ventricular wall motion • Histologically, fibrosis accompanied by cardiomyocyte abnormality (variation in cardiomyocyte size, etc.) and inflammatory cell infiltration (leukocytes in myocardial tissue ≥14/mm2 with CD3-positive T cells ≥7/mm2) • No cardiomyocyte injury (degeneration/necrosis accompanied by encroachment of inflammatory cells at the perimeter of cardiomyocytes)
Inflammatory dilated cardiomyopathy	Not defined		• Subgroup of dilated cardiomyopathy • Histologically characterized by inflammatory cell infiltration (leukocytes in myocardial tissue ≥14/mm2 with CD3-positive T cells ≥7/mm2) • No cardiomyocyte injury (degeneration/necrosis accompanied by encroachment of inflammatory cells at the perimeter of cardiomyocytes) • Conceptually included in chronic inflammatory cardiomyopathy
Chronic myocarditis	Myocarditis >3 months (∼several months) after onset	Myocarditis >3 months after onset	Not described	Myocarditis ≥30 days after onset
	• Histologically characterized by mononuclear cell infiltration (not defined by immunohistochemistry)/ aggregation (≥5 cells/HPF) • Cardiomyocyte injury (degeneration/necrosis accompanied by encroachment of inflammatory cells at the perimeter of cardiomyocytes)	• Histologically, fibrosis accompanied by cardiomyocyte abnormality (variation in cardiomyocyte size, etc.) and inflammatory cell infiltration (leukocytes in myocardial tissue ≥14/mm2 with CD3-positive T cells ≥7/mm2) • Not described regarding cardiomyocyte injury	• Histologically characterized by inflammatory cell infiltration • No cardiomyocyte injury (degeneration/necrosis accompanied by encroachment of inflammatory cells at the perimeter of cardiomyocytes) • Transitional phase between acute myocarditis and chronic inflammatory cardiomyopathy

There has been long-standing debate regarding the Dallas criteria, including low diagnostic sensitivity and lack of correlation with prognosis.^37,38 The publication of the European Society of Cardiology (ESC) Position Statement,⁴ based on the Marburg consensus, setting the quantitative threshold of >14 mononuclear leukocytes/mm² on EMB samples with the presence of >7 T lymphocytes/mm², was meant to increase the sensitivity of EMB in myocarditis diagnosis. Criteria for quantification of infiltrating inflammatory cells in the myocardium were incorporated into the histological diagnosis of myocarditis (ESC criteria),⁴ independently of the Dallas criteria. In Europe, myocarditis is defined as inflammatory disease of the myocardium, with or without associated myocyte damage/necrosis, and inflammatory cardiomyopathy is defined as myocarditis in association with cardiac dysfunction.^4,15 The Expert Consensus Statement reported in 2020 has to some extent consolidated the terminology, definitions, and concepts.⁵ Nevertheless, the pathological diagnostic criteria for myocarditis in clinical practice differ between pathologists, countries and regions, and universal guidelines for myocarditis have not yet been established.

According to a survey by the Society of Cardiovascular Pathology and the European Society of Cardiovascular Pathology, 31.1% of pathologists in Europe used only the Dallas criteria, 44.4% used both the Dallas and ESC criteria, and 17.8% used only the ESC criteria for the pathological diagnosis of myocarditis, compared with 75.6%, 13.3% and 2.2% respectively in North America.³⁹ This has led to fragmentation and gaps in clinical guidelines, and the diagnostic criteria for myocarditis still differ internationally.

Definition of Chronic Active Myocarditis

There are reports emerging of patients with DCM-like presentations who exhibit ongoing myocardial inflammation and cardiomyocyte injury, associated with worsening HF.⁴⁰ Moreover, a Japanese multicenter retrospective study of 261 cases of DCM demonstrated that a higher density of CD3-positive T-lymphocyte infiltration in myocardial tissue correlated with worse clinical outcomes.¹⁹ These findings suggest that some patients diagnosed with DCM have persistent myocardial inflammation that contributes to disease progression.

Given this background, the 2023 revised guidelines for the diagnosis and treatment of myocarditis issued by the JCS incorporate international trends while addressing unmet clinical needs. The guidelines introduce a definition of “chronic active myocarditis” as a high-risk condition characterized by persistent myocardial inflammation during the chronic phase, evidenced by both inflammatory cell infiltration and cardiomyocyte injury (necrosis or degeneration) adjacent to these cells (Table 1).¹¹ This definition relies primarily on findings from EMB. Nevertheless, recognizing the limitations of biopsy, such as sampling errors, the guidelines propose supplementary criteria to identify chronic active myocarditis clinically: (1) persistent elevation of high-sensitivity cardiac troponin levels, (2) infiltration of ≥24 CD3-positive T cells/mm² (5.8 cells/HPF) in myocardial tissue or (3) positive immunostaining for tenascin C with a mouse monoclonal antibody (clone 4C8MS) in myocardial tissue (if available).⁴¹ In cases of negative biopsy evidence of cardiomyocyte injury, close monitoring is warranted to evaluate the potential for chronic active myocarditis.¹¹

Diagnosis

The pivotal factor in the diagnosis of myocarditis is maintaining a heightened level of clinical suspicion. The initial evaluation of myocarditis begins with non-invasive assessments, including blood tests, electrocardiography, and echocardiography, guided by symptoms and clinical signs suggestive of the condition. Next, coronary artery disease should be ruled out using coronary computed tomography or coronary angiography. In appropriately equipped facilities, EMB can be performed, as it remains a cornerstone diagnostic modality (Class IIa recommendation).¹¹

A major recent advancement in the diagnosis of myocarditis is the increasing evidence supporting the use of CMR, which is now a cornerstone in the diagnostic process. CMR enables non-invasive assessment of myocardial morphology, wall motion, and tissue characteristics. For acute myocarditis, CMR-based imaging diagnosis follows the 2018 revised Lake Louise Criteria,⁹ which are divided into 2 main categories: (1) T2-based criteria, which assess myocardial edema, and (2) T1-based criteria, which detect myocardial injury. A diagnosis of myocarditis is established when both criteria are positive. Studies have reported that myocardial edema persists for up to 4 weeks after the onset of acute myocarditis, making CMR within 2–3 weeks of onset ideal for reliably assessing active inflammation.

In contrast, the diagnostic accuracy of CMR diminishes in chronic myocarditis cases that are >3 months after onset.^9,42,43 This limitation highlights the increasing importance of EMB in diagnosing chronic active myocarditis and chronic inflammatory cardiomyopathy based on the proposed criteria. When the criteria for chronic active myocarditis are met, careful follow-up is essential, including intensified HF and arrhythmia management. In fact, even under optimal HF treatment, some cases of patients with progressive LV ejection fraction (LVEF) decline and persistently elevated troponin levels strongly suggest chronic active myocarditis based on the findings of EMB. For such patients, although they are in the chronic phase of myocarditis, a slight elevation in T2 values on CMR is observed.^40,44 Furthermore, these values improve alongside LVEF recovery following immunosuppressive therapy.⁴⁰ Given that myocardial necrosis and fibrosis, rather than edema, predominate in the subacute and chronic phases of myocarditis, T2 mapping may fail to detect ongoing myocardial inflammation.⁴⁵ Nevertheless, T2 mapping provides quantitative and non-invasive measurements, possibly making it a valuable tool for monitoring disease progression and treatment response after immunosuppressive therapy. This underscores the importance of a multimodal diagnostic approach, including CMR and EMB, to optimize the management of patients with chronic active myocarditis. Figure 1 illustrates the characteristic features of chronic active myocarditis and chronic inflammatory cardiomyopathy, and representative cases are shown in Figures 2–4.

Figure 1.

Representative clinical phenotypes of the chronic phase of myocarditis. (Left) Features on CMR of chronic active myocarditis: the LV is dilated, with normal thickness and a slightly high signal on T2-weighted images suggesting edema. Histology shows lymphocytic myocarditis with myocyte necrosis and diffuse mononuclear cell infiltrates by hematoxylin-eosin and immunohistological staining of CD3-positive T cells. (Right) Features on CMR of chronic lymphocytic cardiomyopathy: the LV is dilated, with normal thickness and normal signal intensity on T2-weighted images. Histopathology shows chronic inflammatory cardiomyopathy typically presenting fibrosis within areas with inflammatory cellular infiltrates. *Degeneration/necrosis accompanied by encroachment of inflammatory cells at the perimeter of cardiomyocytes. CMR, cardiac magnetic resonance; GDMT, guideline-directed medical therapy; LV, left ventricle; LVEF, left ventricular ejection fraction.

Figure 2.

Clinical and histopathological features of a patient with chronic inflammatory cardiomyopathy. A 68-year-old man with reduced LVEF had been previously diagnosed with mixed connective tissue disease. (A) Echocardiographic image shows a severely dilated LV chamber with reduced LVEF (4-chamber view). (B) CMR shows linear mid-wall late gadolinium enhancement in the basal-inferior wall (short-axis view, arrowheads). (C) T2-weighted CMR shows no high signal intensity (short-axis view). (D) Subendocardial and interstitial fibrosis present in the endomyocardial biopsy specimen (Masson trichrome staining). (E,F) Enlarged views of (D). (E) Cardiomyocytes are mildly swollen and irregular in size (H&E). (F) Scattered infiltration of CD3-positive T-lymphocyte (CD3-positive T cells >7/mm²) not accompanied by definite signs of cardiomyocyte injury, showing negative tenascin C (4C8) staining (inset F). CMR, cardiac magnetic resonance; LV, left ventricle; LVEF, left ventricular ejection fraction.

Figure 3.

A 43-year-old man presented with heart failure. Clinical and histopathological features of chronic inflammatory cardiomyopathy requiring careful follow-up to consider the possibility of chronic active myocarditis. (A) Echocardiographic image 3 months after the onset of heart failure shows a severely dilated LV chamber with reduced LVEF (4-chamber view). (B) CMR shows late gadolinium enhancement with an endocardial and midmural pattern (4-chamber view, arrowheads). (C) T2 mapping in CMR shows myocardial edema (native T2 55–57 ms, bulls-eye map). (D) Replacement fibrosis suggests post-inflammatory changes (Masson trichrome staining). (E,F) Enlarged views of (D). (E: H&E, F: CD3 immunostaining). There is inflammation (CD3-positive T cells >24/mm²) not accompanied by definite signs of cardiomyocyte injury, and a focal tenascin C (4C8)-positive area (inset F, tenascin C immunostaining). CMR, cardiac magnetic resonance; LV, left ventricle; LVEF, left ventricular ejection fraction.

Figure 4.

A 62-year-old man after acute myocarditis shows clinical and histopathological features of chronic active myocarditis. (A) Echocardiographic image 30 days after acute myocarditis shows a severely dilated LV chamber with depressed LVEF (long-axis view). (B) CMR shows late gadolinium enhancement with an epicardial and midmural pattern (4-chamber view, arrowheads). (C) T2 mapping in CMR shows myocardial edema (native T2 60-63 ms, bulls-eye map). (D) Dense and loose mixed fibrosis suggests subacute inflammatory changes (Masson trichrome staining). (E,F) Active inflammation accompanied by signs of cardiomyocyte injury Enlarged views of (D). (E: H&E, F: CD3 immunostaining). CMR, cardiac magnetic resonance; LV, left ventricle; LVEF, left ventricular ejection fraction.

Treatment

Chronic active myocarditis and inflammatory cardiomyopathy represent challenging clinical conditions characterized by ongoing myocardial inflammation, persistent immune-mediated damage, and progressive myocardial dysfunction. These disorders often lead to significant morbidity and mortality, primarily due to HF and life-threatening arrhythmias. Optimal management requires a multidisciplinary approach, integrating pharmacological therapy, device implantation, and, in some cases, advanced therapies such as mechanical circulatory support or heart transplantation.^5,11 The primary treatment strategy for myocarditis involves hemodynamic support during the acute phase and pharmacological therapy for HF during the chronic phase. As mentioned before, myocardial injury in myocarditis arises from 2 main mechanisms: direct injury due to triggers such as viral infections, and secondary injury mediated by immune and inflammatory responses, including the cytokine cascade. Accordingly, therapeutic approaches targeting the underlying causes, including immunosuppressive therapy, have been proposed.

Conventional Therapy

HF is managed according to established HF guidelines and statements,^46–51 but specific considerations are required due to the underlying inflammatory process. Standard HF therapies include β-blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and mineralocorticoid receptor antagonists.⁵² Emerging evidence supports the role of sodium-glucose cotransporter 2 inhibitors in improving outcomes in patients with HF regardless of LVEF, even in inflammatory cardiomyopathy.⁴⁷ Diuretics remain essential for symptom management of volume overload. For patients with refractory HF despite optimal medical therapy, mechanical circulatory support devices such as ventricular assist devices may be considered, and heart transplantation remains a definitive option for endstage HF. Regular follow-up with echocardiography, CMR, and biomarker assessments (e.g., N-terminal pro-B-type natriuretic peptide, troponin) is essential to evaluate cardiac function, inflammation status, and therapeutic response.¹¹

Arrhythmias arise from the myocardial inflammation, fibrosis, and electrical remodeling, presenting as atrial fibrillation, ventricular tachycardia, premature ventricular contractions, and conduction abnormalities. Beta-blockers remain the first-line agents for managing both ventricular and supraventricular arrhythmias, but amiodarone is preferred for ventricular arrhythmias due to its efficacy and safety profile in HF. Anticoagulation is essential in patients with atrial fibrillation or reduced EF to prevent thromboembolic events. Device therapy, including implantable cardioverter-defibrillators for secondary prevention and cardiac resynchronization therapy for patients with LV dyssynchrony, plays a critical role in reducing arrhythmic risk and improving cardiac function. Catheter ablation may be considered in drug-refractory atrial fibrillation or scar-mediated ventricular tachycardia. Long-term follow-up with ambulatory ECG monitoring and regular device checks is necessary to assess arrhythmia burden and device functionality. Effective management of HF and arrhythmias requires close collaboration among cardiologists, electrophysiologists, immunologists, and cardiac imaging specialists. Personalized treatment plans should be based on clinical severity, inflammatory activity, and the individual patient’s characteristics. Future research focusing on novel biomarkers, advanced imaging techniques, and targeted therapies is essential to further improve outcomes in these challenging conditions.

Condition-Specific Therapy

Numerous observational studies and randomized controlled trials have investigated the efficacy of immunosuppressive therapy in patients with the chronic phase of myocarditis or DCM (Table 2).^53–59

Table 2.

Summary of Studies on Immunosuppressive Therapy for Chronic Phase of Myocarditis

Study name/ Authors	Year	Study design/ immunosuppressive drugs	Sample size	Diagnosis	Outcome measures	Main results
Prednisone trial for DCM53	1989	RCT: Prednisolone	102	DCM	Primary: LVEF after 3 months	Improvement
Wojnicz et al.54	2001	RCT: Prednisolone+ Azathioprine	84	Inflammatory DCM (increased HLA expression)	Primary: Death, cardiac transplantation, rehospitalization (composite); Secondary: LVEF after 3 months	Primary: No significant difference; Secondary: Improvement
Frustaci et al.55	2003	Retrospective: prednisolone+ azathioprine	41	Patients developing heart failure post- acute myocarditis (unknown etiology)	LVEF at 1 year	Improvement in virus-negative cases
TIMIC trial56	2009	RCT: prednisolone+ azathioprine	85	Inflammatory DCM (virus-negative)	Primary: Left ventricular function (LVEF, LVDd) after 6 months	Improvement
Merken et al.57	2018	Retrospective (propensity score matching): prednisolone+ azathioprine or cyclosporine	209	Inflammatory DCM (≥14 inflammatory cells/mm2)	Long-term outcomes (survival without cardiac transplantation); LVEF after 1 year	Improvement in long-term outcomes and LVEF
20-year follow-up of the TIMIC trial58	2022	Post-hoc analysis of RCT (1 : 2 matching for control group): prednisolone+ azathioprine	Treatment group: 85 Control group: 170	Inflammatory DCM (virus-negative)	Primary: Cardiac death or transplantation after 20 years (composite); Secondary: Left ventricular function (LVEF, LVDd) after 20 years	Primary: Improvement; Secondary: Improvement
Caforio et al.59	2024	Prospective (propensity score matching): Various immunosuppressive drugs	Treatment group: 91 Control group: 267	Myocarditis (biopsy-confirmed, including acute and chronic)	Primary: Long-term outcomes (survival without death or cardiac transplantation); Secondary: Improvement in left/right ventricular function	Primary: No significant difference; Secondary: Improvement

DCM, dilated cardiomyopathy; HLA, human leukocyte antigen; LVDd, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; RCT, randomized controlled trial.

The Myocarditis Treatment Trial, which is the first clinical study investigating the effects of immunosuppressive therapy in addition to optimal medical therapy in 111 patients with histologically diagnosed acute myocarditis, did not show survival or functional benefits in patients receiving immunosuppressive therapy compared to those receiving optimal medical therapy alone.⁶⁰ However, EMB in that trial were analyzed exclusively based on the histological Dallas criteria, without incorporating viral genome analysis in the myocardial tissue samples. This limitation might have resulted in the inclusion of patients with active viral infections, potentially affecting the observed outcomes and the interpretation of the efficacy of immunosuppressive therapy.

Notably, in a retrospective cohort study, an immunological and virological assessment of patients with lymphocytic myocarditis undergoing immunosuppressive therapy revealed a 90% treatment success rate among virus-negative patients.⁵⁶ Conversely, 85% of non-responders were found to have detectable viral genomes in their myocardial tissue,⁵⁶ suggesting that viral persistence may play a significant role in resistance to immunosuppressive therapy and emphasizing the value of viral genome analysis in therapeutic decision-making. Furthermore, the Tailored Immunosuppression in Virus-Negative Inflammatory Cardiomyopathy (TIMIC) trial,⁵⁶ a randomized double-blind study, aimed to evaluate the efficacy of immunosuppressive therapy using prednisone and azathioprine in 85 patients with biopsy-proven virus-negative active myocarditis and chronic HF refractory to optimal medical therapy, compared with a placebo group. The results demonstrated a significant improvement in LVEF in 88% of patients receiving immunosuppressive therapy, whereas 83% of patients in the placebo group had progressive LV dysfunction. Moreover, follow-up EMB revealed the resolution of inflammatory infiltrates in patients who responded positively to immunosuppressive therapy. A 20-year follow-up study of the same cohort further reinforced these findings, confirming the short- and long-term efficacy of immunosuppressive therapy.⁵⁸ Additionally, the benefits extended even to patients with severely impaired baseline LV function and proved effective in preventing relapses in immune-mediated myocarditis.⁵⁸ Caforio et al. also evaluated the long-term efficacy and safety of tailored immunosuppressive therapy in biopsy-proven immune-mediated myocarditis, regardless of histology or clinical presentation.⁵⁹ In their study using a propensity score-weighted analysis, 91 patients receiving immunosuppressive therapy were compared with 267 on optimal medical therapy. Patients receiving immunosuppressive therapy, despite lower baseline biventricular function and higher risk profiles, showed comparable survival rates and functional outcomes to patients with optimal medical therapy at long-term follow-up.

Given these findings, immunosuppressive therapy may improve clinical outcomes in patients with the chronic phase of viral-negative myocarditis, including chronic active myocarditis or chronic inflammatory cardiomyopathy. For the safety of immunosuppressive treatment, the ESC Position Statement recommends viral genome analysis of EMB samples, and that immunosuppression should be started only after ruling out active infection.⁴

In the past 2 decades, parvovirus B19 and human herpes virus 6 (HHV6) have been more frequently detected in EMB samples from patients with myocarditis.¹² Parvovirus B19 deoxyribonucleic acid (DNA) is also found in the majority of cases of non-inflammatory cardiomyopathy (ischemic or valvular heart disease) with low copy numbers, bringing the role of parvovirus B19 as a pathogenic agent or innocent ‘bystander’ into question.⁶¹ Tschöpe et al. suggest that patients with inflammatory cardiomyopathy, regardless of parvovirus B19 genome persistence, can achieve significant improvements in myocardial inflammation and LV function after immunosuppressive therapy without increasing the viral DNA copy number.⁶² In addition, in selected symptomatic patients with cardiac HHV6 DNA copy numbers <500 copies/µg cardiac DNA and without signs of active systemic HHV6 infection, immunosuppressive therapy was found to be effective and safe.⁶³ Differentiating between the detected virus being a bystander or the actual etiologic agent remains challenging, although a viral DNA copy number that exceeds a threshold of 500 copies/µg has been proposed as the cause of myocarditis with regard to parvovirus B19 and HHV6.⁶¹ Further research is required to better define the virus-specific cutoff values to distinguish innocent bystanders from real pathogenic agents and to confirm the implications for patient management.⁶⁴

Although a consensus has not been reached, for high-risk patients such as those with progressive LV dysfunction where autoimmune mechanisms are strongly suspected, a strategy involving the confirmation of negative viral genome findings in myocardial tissue followed by immunosuppressive therapy has been proposed.⁶⁵ Evidence supporting this approach is accumulating, with reports of successful outcomes in some cases.⁴⁰ Further research is warranted to establish the role of immunosuppressive therapy in the management of chronic active myocarditis.

Alternative condition-specific therapies for patients with virus-negative or autoimmune inflammatory cardiomyopathies include autoantibody removal through immunoadsorption, followed by intravenous immune globulin therapy (IVIG). A small-scale randomized study of IVIG in patients with parvovirus B19-related inflammatory cardiomyopathy or chronic myocarditis showed that IVIG did not improve cardiac function, exercise tolerance, or quality of life.⁶⁶ A large multicenter study is currently underway (Multicenter Study of Immunoadsorption in Dilated Cardiomyopathy; IASO-DCM [NCT00558584]), focusing on patients with DCM to further evaluate these approaches.

Given the role of viral infection in the pathogenesis of viral myocarditis, antiviral therapy also holds theoretical potential. Myocardial injury during the early stages of myocarditis is caused by viral entry and replication in cardiomyocytes.⁶⁷ Therefore, early administration of antiviral drugs upon confirmation of viral genome positivity may be beneficial. For instance, early administration of oseltamivir has been reported to reduce the mortality rate for viral myocarditis caused by influenza A virus.¹¹ However, no antiviral therapies with proven efficacy for myocarditis have been established. Consequently, antiviral therapy is not currently recommended for the treatment of myocarditis.^4,5,11

Challenges and Future Directions

As discussed, the definitions and concepts of myocarditis have evolved significantly, and the JCS has recently updated its guidelines. However, a major challenge lies in translating these conceptual advancements into effective therapeutic applications. In recent years, there has been progress in research, particularly in Europe, focusing on individualized treatments guided by viral genome polymerase chain reaction evaluation in myocardial tissue. Immunosuppressive therapy has shown promise in patients with the chronic phase of myocarditis and negative viral genomes. Conversely, emerging studies suggest the potential role of antiviral therapy in patients with positive viral genomes. Despite these developments, both of these individualized therapeutic approaches remain in their preliminary stages. Additionally, viral infections are known to exhibit geographical variation, and the epidemiological profile of viral infections in patients with myocarditis in Japan remains to be fully elucidated. High-quality clinical studies are urgently needed to establish robust evidence base and drive the development of effective, targeted treatment strategies.

Acknowledgments

None.

Sources of Funding

This was supported by a grant from the Japan Agency for Medical Research and Development (AMED) under grant number 24ek0109683h0002 (to T.N., K.O.-O., K.I.-Y.).

Disclosures

T.N. received research grants from Pfizer Inc., Mitsubishi Tanabe Pharma Corp., and Roche Diagnostics K.K., and honoraria from Kyowa Kirin Co., Ltd., Bayer Yakuhin, Ltd., Viatris Inc., Nippon Boehringer Ingelheim Co., Ltd., and Bristol-Myers Squibb K.K. T.A. received a research grant from Daiichi Sankyo Co., Ltd.; scholarship funds from Biotronik Japan Co., Ltd., Medtronic Japan Co., Ltd., Win International Co., Ltd., Medical System Network Co., Ltd., and Hokuyaku Takeyama Holdings, Inc.; and honoraria from Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Boehringer Ingelheim Japan Co., Ltd., Bayer’s Pharmaceuticals Co., Ltd., and Bristol-Myers Squibb Co., Ltd. The remaining authors declare no conflicts of interest.

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