Arrhythmic Burden After Myocarditis: From Molecular Mechanisms to Therapeutic Strategies

Myocarditis is an inflammatory disease of the myocardium characterised by a wide spectrum of clinical presentations and outcomes.^1,2 It can result from various triggers, including viral infections, autoimmune reactions or exposure to toxic agents. Endomyocardial biopsy remains the diagnostic gold standard, providing histological, immunohistochemical and molecular insights, particularly in high-risk cases.^3,4

The variable clinical course and limited use of endomyocardial biopsy do not allow for the establishment of the true incidence, which is estimated at approximately 22 cases per 100,000 individuals per year. Furthermore, myocarditis is recognised as an important cause of sudden cardiac death (SCD) among young individuals, accounting for 6–10% of cases in autopsy-based series.^5,6

The clinical course of myocarditis is highly heterogeneous, ranging from asymptomatic or subclinical forms to acute heart failure (HF), life-threatening arrhythmias and SCD.⁷ While acute myocarditis is often self-limiting, a subset of patients may progress to chronic inflammatory cardiomyopathy, characterised by persistent myocardial inflammation, structural remodelling and long-term adverse outcomes.⁸

Initial evaluation includes clinical assessment, ECG, serum biomarkers (notably high-sensitivity cardiac troponins) and transthoracic echocardiography. Although transthoracic echocardiography lacks sensitivity for diagnosing myocarditis, it remains essential to rule out alternative causes and to identify suggestive features, such as regional wall motion abnormalities and global longitudinal strain reduction.²

The diagnostic workup should also consider conditions that can mimic myocarditis. The clinical presentation often overlaps with other cardiovascular disorders, particularly acute coronary syndrome, pericarditis and various cardiomyopathies, which may present with chest pain, ECG abnormalities, elevated cardiac biomarkers and impaired ventricular function.^9,10 Since these clinical features can be highly similar, a correct clinical assessment – encompassing medical history (e.g. recent fever or preceding infections), careful evaluation of symptoms, 12-lead ECG interpretation, and the use of additional diagnostic imaging and instrumental tests – is essential to better characterise the underlying condition and to guide appropriate management.

In this regard, arrhythmias represent a significant, but often overlooked, manifestation of myocarditis, occurring in both acute and chronic phases.^11,12 Ventricular arrhythmia (VA) may develop during the active inflammatory phase or later, when fibrotic remodelling and non-ischaemic scar formation create a structural substrate favouring re-entrant circuits. In some patients, malignant VA may be the first and only clinical manifestation of myocarditis, even in the absence of overt left ventricular (LV) dysfunction.¹²

The 12-lead ECG is crucial in this setting, as it enables discrimination between a benign ventricular ectopic burden and arrhythmias suggestive of an underlying pathological substrate. Careful interpretation of ECG signs is therefore fundamental, as it provides essential information for distinguishing idiopathic from pathological patterns. Several ECG indices have been proposed to predict the site of origin of premature ventricular complexes (PVCs), thereby aiding risk stratification and guiding management.¹³ Notably, novel parameters, such as the RV1–V3 transition ratio, have shown improved accuracy in differentiating right- from left-sided outflow tract PVCs, enhancing the diagnostic value of surface ECG.¹⁴

Cardiac MRI has emerged as the preferred non-invasive diagnostic tool due to its superior tissue characterisation, according to the 2018 revised Lake Louise Criteria. These criteria require at least one T2-based marker of myocardial oedema and one T1-based marker of myocardial injury or fibrosis. Typical late gadolinium enhancement patterns, usually subepicardial or mid-wall, help differentiate myocarditis from ischaemic heart disease. Additional advances, such as T1 and T2 mapping, further improve diagnostic accuracy.

About half of the cases of evidence-based medicine-confirmed acute or active myocarditis show resolution within the first 2–4 weeks. However, approximately 25% of patients may experience ongoing cardiac dysfunction, and between 12 and 25% can worsen, potentially resulting in death or progression to end-stage dilated cardiomyopathy (DCM) requiring heart transplantation. The short- and long-term outcomes of myocarditis are influenced by its underlying cause, clinical presentation and the stage of disease. Accordingly, effective risk stratification at the initial clinical assessment is essential to guide appropriate management.²

Despite its clinical relevance, post-myocarditis arrhythmogenesis remains poorly understood, driven by complex biological mechanisms and lacking clear management guidelines. Therefore, this review aims to critically explore the arrhythmic burden associated with myocarditis, a frequently underdiagnosed condition that may evolve into dramatic consequences, particularly in young individuals. Furthermore, current challenges in risk stratification and the need for a more structured and individualised clinical approach are explained.

Phasic Evolution of Cardiac Remodelling in Myocarditis: Acute, Reparative and Chronic Stages

The molecular disarrangements driving arrhythmic burden in myocarditis are complex and multifaceted, evolving from acute inflammatory damage to chronic structural remodelling and potential progression to DCM. The interplay among cardiomyocytes, fibroblasts, endothelial cells, smooth muscle cells and immune components contributes to a heterogeneous pathophysiological landscape in which acute inflammation evolves into chronic fibrosis; thus, perpetuating the risk of arrhythmic events.^15,16

Inflammatory Phase: Acute Cellular and Molecular Dysfunction

During the acute phase of myocarditis, the inflammatory response triggers a cascade of molecular events that perturb cardiac electrical stability. Viral infections, particularly from cardiotropic viruses, initiate cytolytic damage to cardiomyocytes, leading to apoptosis and necrosis.¹⁷ This damage is not only directly virus-induced, but also mediated by immune mechanisms, where cytotoxic T-cells and natural killer cells target infected myocytes. The resulting cellular breakdown releases intracellular contents that act as damage-associated molecular patterns, exacerbating the inflammatory response.¹⁵

Cardiomyocytes, despite constituting a significant portion of the myocardial volume, have a limited capacity for regeneration. Upon viral infection, these cells may undergo various fates, including apoptosis, immune-mediated necrosis or persistent infection without immediate cell death.¹⁸ Apoptosis occurs frequently in small clusters and can result in conduction abnormalities and electrical uncoupling. The disruption of gap junctions, particularly the downregulation of connexin 43, impairs intercellular electrical connectivity. This alteration is often mediated by inflammatory kinases, including protein kinase C and p38 mitogen-activated protein kinase, which phosphorylate connexin 43, leading to reduced gap junction conductance.¹⁹

Endothelial cells (ECs) also undergo significant alterations during the inflammatory phase. Normally maintaining vascular homeostasis, ECs become activated under inflammatory stress, increasing vascular permeability and upregulating adhesion molecules, such as E-selectin, intercellular adhesion molecule 1 and vascular cell adhesion molecule 1.²⁰ This activation facilitates immune cell infiltration into the myocardium, further intensifying the inflammatory milieu. Viral persistence within ECs exacerbates dysfunction, promoting microvascular ischaemia and coronary vasospasm, with elevated levels of endothelin 1 contributing to abnormal vasomotor responses.^21,22

In myocarditis contexts, vascular smooth muscle cells (VSMCs) can undergo significant functional alterations due to the hypercoagulable state induced by infection. The activation of protease-activated receptors, particularly protease-activated receptor 1 and protease-activated receptor 2, on VSMCs mediates a pro-thrombotic and pro-inflammatory response.²³ This activation is often triggered by coagulation-derived proteases, such as thrombin and factor Xa, which affect VSMCs’ function and contribute to pathological vascular remodelling.²⁴ Moreover, activated VSMCs can promote intravascular coagulation and localised ischaemic damage, increasing the risk of electrical instability in the myocardium.²⁵

The immune response itself, involving both innate and adaptive mechanisms, contributes to the arrhythmic risk. Innate immunity, mediated by Toll-like receptors, recognises viral components and activates nuclear transcription factors, leading to cytokine release.²⁶ Adaptive immunity, predominantly driven by CD4⁺ and CD8⁺ T-cells, targets infected cardiomyocytes, but can also mistakenly attack uninfected cardiac tissue due to molecular mimicry.^27,28 Excessive immune activation, particularly from CD8⁺ cytotoxic T-cells, can result in persistent myocardial damage and fibrosis, forming a substrate for arrhythmias.²⁹ Finally, conduction tissue can be involved as well, and its selective inflammation can be a trigger for re-entrant tachyarrhythmias arising from Purkinje fibres.

Reparative Phase: Fibrosis and Structural Remodelling

As the inflammatory phase subsides, myocarditis may convert into a chronic state characterised by structural remodelling and fibrosis, which significantly increases arrhythmic risk.³⁰ The formation of fibrotic tissue, often located in the LV sub-epicardium or mid-wall regions, disrupts the orderly propagation of electrical impulses. This fibrotic remodelling is primarily driven by activated fibroblasts, which proliferate and secrete extracellular matrix (ECM) proteins, including collagen, in response to pro-fibrotic signals, such as transforming growth factor-β.³¹

Cardiac fibroblasts (CFs) play a crucial role in the progression of chronic myocarditis to DCM. During myocarditis, CFs can become viral reservoirs, particularly when infected by cardiotropic viruses, such as coxsackievirus B3.³² Studies have shown that CFs support higher viral replication compared with cardiomyocytes, sustaining viral persistence and ongoing inflammation. These infected cells actively contribute to the inflammatory environment by secreting pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF-α), interleukin-6 (IL-6) and chemokines (e.g. monocyte chemoattractant protein 1), attracting immune cells and amplifying myocardial injury.³³

As chronic inflammation progresses, CFs produce matrix metalloproteinases that degrade ECM components, leading to tissue remodelling, fibrosis and scar formation. This ongoing ECM deposition results in myocardial stiffening, forming regions of conduction block that promote re-entrant arrhythmias. Moreover, fibrosis disrupts electrical coupling between cardiomyocytes through downregulation of ion channels, such as Kv4.2 and Nav1.5, and therefore impairs conduction and increases the risk of life-threatening VAs, such as sustained ventricular tachycardia (VT) and VF.^30,34

The persistent activation of CFs, driven by chronic immune responses and cytokine signalling (notably TNF-α and IL-1β), maintains ECM synthesis and fibrosis. As a result, the myocardium becomes increasingly stiff and dilated, compromising contractility and evolving into DCM. This structural transformation not only impairs cardiac function, but also establishes a substrate prone to arrhythmogenesis, emphasising the pivotal role of fibroblast-mediated remodelling in the chronic phase of myocarditis.^22,31

Chronic Inflammation and Autoimmunity: Prolonged Arrhythmogenic Risk

Chronic myocarditis may persist as a low-grade inflammatory state, maintaining an arrhythmogenic substrate through ongoing immune activation.³⁵ In some cases, chronic active myocarditis is characterised by retained viral genomes and persistent infiltration by immune cells, particularly CD4⁺ T-helper 17 and regulatory T-cells. While T-helper 17 cells promote fibrosis through IL-17 secretion, regulatory T-cells, despite their regulatory role, may indirectly enhance fibrotic processes via transforming growth factor-β signaling.^36,37 Autoantibodies against cardiac proteins and ion channels may develop due to molecular mimicry between viral antigens and myocardial components. These autoantibodies can disrupt normal electrophysiological function, contributing to long-term arrhythmogenic potential.³⁴

Vascular Involvement and Coronary Dysfunction

Endothelial dysfunction is a critical aspect of chronic myocarditis, driven by persistent inflammatory signals and the persistence of viral genomes within ECs. This dysfunction compromises coronary perfusion through impaired endothelium-dependent vasodilation and increased vasospasm, largely mediated by endothelin 1 and thromboxane. The resulting reduction in coronary flow reserve predisposes to ischaemic events and secondary arrhythmias, particularly in the presence of fibrotic myocardial scars.³⁸ VSMCs contribute to the hypercoagulable state observed in chronic myocarditis, with ongoing activation of coagulation pathways leading to microthrombosis.^39,40 This vascular dysfunction not only compromises myocardial perfusion, but also exacerbates ischaemic arrhythmias, particularly in patients with coexisting coronary artery disease.⁴¹

Electrophysiological Remodelling and Arrhythmias in Myocarditis

The development of arrhythmias in myocarditis is a complex process driven by a combination of electrophysiological remodelling and ion channel dysfunction. VAs depend on ion channel dysfunction and disrupted cardiac electrical conduction, both of which are exacerbated by systemic and localised inflammation (Table 1 ). The pathophysiological mechanisms underlying these arrhythmias can be broadly categorised into triggered activity and re-entrant circuits, which are influenced by both structural and electrophysiological changes.⁴²

Pathways of Electrical and Ion Channel Dysfunction

In myocarditis, inflammation significantly affects the electrophysiological properties of the myocardium, leading to profound alterations in ion channel function. Inflammatory cytokines modulate the expression and function of Na⁺ and K⁺ channels, resulting in heterogeneous repolarisation and an increased propensity for arrhythmic events. The disruption in ionic homeostasis, particularly involving Na⁺ and K⁺ channels, underlies many of the observed arrhythmias.⁴³

Triggered Activity

Triggered activity in myocarditis predominantly arises from two mechanisms: early afterdepolarisations and delayed afterdepolarisations. Early afterdepolarisations occur when prolonged action potential duration (APD) facilitates the reactivation of L-type Ca²⁺ channels during phases 2 or 3, often triggered by Ca²⁺ influx or disrupted repolarisation. This mechanism is commonly associated with prolonged APD, which also steepens the restitution curve, increasing the risk of electrical instability, especially during rapid heart rate accelerations. Delayed afterdepolarisations, in contrast, are driven by intracellular Ca²⁺ overload. Spontaneous Ca²⁺ release from the sarcoplasmic reticulum through ryanodine receptors activates the sodium-calcium exchanger, leading to membrane depolarisation and ectopic beat formation. The interplay between increased intracellular Ca²⁺ and sodium-calcium exchanger activation forms a critical arrhythmogenic substrate, particularly in inflamed myocardial tissue.^44,45

Re-entrant Circuits

Re-entry is another fundamental mechanism underlying myocarditis-related arrhythmias. It can occur in structurally normal myocardium, where phase 2 re-entry emerges due to regional APD dispersion, allowing electrical propagation from active to suppressed myocardial areas, initiating ectopic activity. Alternatively, circus-type re-entry arises when slowed conduction velocity, unidirectional block and an anatomical or functional obstacle create conditions for a circulating wave front. Reduced conduction velocity, often caused by interstitial oedema and altered ECM composition, promotes the formation of re-entrant circuits by prolonged effective refractory period (ERP) resulting in a shortened excitation wavelength and increased susceptibility to VAs.^46,47

Experimental autoimmune myocarditis models have demonstrated significant electrophysiological changes, including prolonged monophasic APD and increased ERP, leading to delayed repolarisation and enhanced arrhythmic risk.⁴⁸

Arrhythmias in Myocarditis

VAs are the most severe and potentially fatal complications of myocarditis, ranging from PVCs to sustained VT and VF. Myocardial oedema, a hallmark of acute inflammation, disrupts local repolarisation and increases APD dispersion, forming a substrate for re-entry, particularly in the LV free wall. Experimental studies have demonstrated that oedema-induced ion channel dysfunction prolongs APD and heightens the risk of early afterdepolarisations, thereby promoting VT and VF.^49,50

Myocarditis can impair atrioventricular (AV) nodal function, resulting in conduction blocks of different degrees. Advanced AV blocks are particularly associated with giant cell myocarditis, cardiac sarcoidosis and bacterial myocarditis. Inflammatory infiltration into the conduction system can cause first-, second- or third-degree AV block. Giant cell myocarditis, characterised by rapid progression and poor prognosis, often presents with advanced AV block in up to 28% of cases.⁵¹

Supraventricular arrhythmias, including AF, can be observed in myocarditis. Sinus tachycardia, a common early manifestation, often results from systemic inflammation and haemodynamic stress related to HF. Inflammation within the atrial myocardium, particularly around the pulmonary veins, can increase automaticity or generate ectopic foci, predisposing to AF. Structural changes in the atria, such as fibrosis and myocyte necrosis, further perpetuate AF. These alterations disrupt the normal conduction pathways, potentially leading to atrial flutter or focal supraventricular tachycardias.^52,53

Ischaemic mechanisms also contribute to VAs in myocarditis. Inflammation may compromise coronary microcirculation through endothelial dysfunction, mural thrombus formation and vasospasm, leading to ischaemia even in the absence of obstructive coronary artery disease. Additionally, autonomic imbalance resulting from inflammation-induced catecholamine release can predispose to electrical instability, increasing intracellular Ca²⁺ and triggering delayed afterdepolarisations.^54,55

Therapeutic Approaches in Myocarditis

The therapeutic management of myocarditis remains challenging due to the heterogeneity of its clinical presentations, and the complex interplay among inflammation, structural remodelling and electrophysiological disturbances. The primary goals are to manage HF, control arrhythmic events and address the underlying aetiology when possible.⁵⁶ Importantly, the impact of therapeutic strategies on the arrhythmic burden should be carefully considered, as some treatments may have proarrhythmic effects or modulate arrhythmogenesis.⁵

Heart Failure Management and Impact on Arrhythmic Risk

HF management in myocarditis follows current guidelines, including the use of diuretics, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers and mineralocorticoid receptor antagonists. Newer drugs, such as angiotensin receptor/neprilysin inhibitor and sodium-glucose cotransporter 2 inhibitors could also be considered in this setting.^57,58 Some of these aforementioned agents not only improve haemodynamics, but also have indirect antiarrhythmic effects by reducing cardiac workload, preventing adverse remodelling and modulating autonomic tone. In severe cases with haemodynamic instability, advanced supportive measures, such as extracorporeal membrane oxygenation, may be necessary.⁵⁹ While extracorporeal membrane oxygenation stabilises circulation, it does not directly address arrhythmogenic substrates and may require concurrent antiarrhythmic therapy, especially in patients prone to VT or VF.⁶⁰

Anti-inflammatory and Immunomodulatory Therapies: Balancing Benefits and Arrhythmic Risk

The role of corticosteroids and other immunosuppressive agents remains controversial. In virus-negative chronic inflammatory cardiomyopathy, immunosuppressive therapy can improve ejection fraction (EF) and reduce LV dilatation.⁶¹ However, its effect on arrhythmias is less clear. Corticosteroids can facilitate the recovery of AV node function, reducing the need for permanent pacing in some cases. In contrast, non-specific immunosuppression may worsen viral replication if active infection persists, potentially increasing arrhythmic risk.⁵¹

High-dose IV immunoglobulin and monoclonal antibodies targeting pro-inflammatory cytokines (e.g. TNF-α inhibitors) may stabilise myocardial tissue and reduce arrhythmic potential. These therapies aim to attenuate autoimmune responses while preserving antiviral defences; thus, potentially lowering the incidence of inflammatory-induced arrhythmias. Notably, TNF-α has been shown to play a dual role in myocarditis: while it promotes disease onset through activation of cardiac endothelial cells and leukocyte recruitment, it also appears to limit disease progression by inducing activation-induced cell death of heart-reactive T-cells in later stages.^62,63

Colchicine may exert indirect antiarrhythmic effects by reducing myocardial inflammation and fibrosis.^64,65 However, nonsteroidal anti-inflammatory drugs have shown mixed results, as their use in myocarditis can sometimes exacerbate myocardial injury and promote arrhythmias, particularly AF.⁶⁶ Thus, the choice of anti-inflammatory therapy must be individualised, considering the potential side-effects.

Antiviral and Aetiology-specific Treatments

In cases where a viral aetiology is identified, antiviral therapies may be considered. For herpesvirus infections, ganciclovir and acyclovir are preferred choices, although their efficacy in myocarditis remains unproven.^50,67 Interferon-β has shown potential in patients with enteroviral or adenoviral myocarditis, improving survival and reducing ventricular dysfunction.^68,69 By reducing viral load and modulating inflammatory pathways, these treatments may indirectly reduce the arrhythmic burden. However, antiviral therapy is generally reserved for confirmed viral myocarditis, as indiscriminate use in virus-negative myocarditis can be harmful.^2,70

Antiarrhythmic Strategies: Targeting Electrical Instability

The management of arrhythmias in myocarditis primarily involves the use of antiarrhythmic drugs, aiming to stabilise cardiac electrical activity, reduce arrhythmic episodes and prevent SCD.⁷¹ Given the inflammatory and structural changes occurring in myocarditis, the choice of antiarrhythmic agents must consider both the specific arrhythmia and the underlying myocardial condition.⁷

β-blockers are the cornerstone of arrhythmia management in myocarditis, especially when sympathetic overdrive contributes to arrhythmogenesis. Metoprolol and carvedilol are commonly used due to their additional benefits on LV function; however, carvedilol demonstrated cardioprotective effects in rat models of autoimmune myocarditis, primarily through its ability to reduce inflammatory cytokine production and its antioxidant activity, unlike metoprolol and propranolol, which did not show similar benefits.⁷² However, β-blockers should be used cautiously in the acute inflammatory phase when severe myocardial depression may be present, as they can exacerbate hypotension and bradyarrhythmias. β-blockers also reduce the incidence of supraventricular arrhythmias, such as AF, by decreasing atrial automaticity and inhibiting catecholamine-induced arrhythmic triggers.^73,74 During myocarditis, long-term use of β-blockers in patients with LV dysfunction can decrease the overall arrhythmic burden by mitigating the adverse effects of sympathetic hyperactivity.^5,56

Amiodarone is frequently used in myocarditis to control both supraventricular and VAs. Its broad antiarrhythmic profile, including K⁺, Na⁺ and Ca²⁺ channel blockade, contributes to reducing arrhythmic episodes. Amiodarone can prolong the APD and ERP, and this mechanism is beneficial in suppressing re-entrant circuits. Due to its minimal negative inotropic effect, amiodarone is often preferred in patients with HF or LV dysfunction. Additionally, its β-blocking properties can reduce sympathetic-induced arrhythmias. However, its long-term toxicity against lungs, liver and thyroid gland necessitates cautious use, particularly in younger patients or those expected to achieve myocardial recovery. Amiodarone is particularly useful when myocarditis manifests with recurrent VT or frequent PVCs, where rhythm control is crucial. It also provides some protection against AF and atrial flutter, which are common in the context of myocarditis-related atrial remodelling.^71,75,76

Sotalol, a Class III antiarrhythmic agent with β-blocking properties, can be considered when amiodarone is not suitable or as an adjunct therapy. It prolongs the APD and increases ERP, reducing the risk of re-entrant arrhythmias. However, sotalol’s proarrhythmic potential, particularly torsade de pointes, must be carefully monitored, especially in patients with prolonged QT interval or electrolyte imbalances common in myocarditis.⁷⁷

As a Class IB antiarrhythmic drug, mexiletine can be added to amiodarone for controlling ventricular ectopy, especially in cases of frequent PVCs or non-sustained VT. Its ability to block Na⁺ channels during the late phase of depolarisation helps stabilise electrical activity in damaged myocardium. However, its use is limited due to gastrointestinal side-effects and potential central nervous system toxicity.⁷⁸

Class IC antiarrhythmic drugs can be used for AF or flutter in structurally normal hearts. However, they are generally avoided in myocarditis due to the increased risk of arrhythmia, especially in patients with ventricular dysfunction or myocardial scarring.^7,79

Verapamil and diltiazem can be considered for rate control in AF, particularly when β-blockers are contraindicated. These agents decrease Ca²⁺ influx during phase 2 of the action potential; thus, reducing the automaticity of atrial and nodal tissues. However, their use should be avoided in patients with significant LV dysfunction due to the risk of negative inotropic effects.⁸⁰

The choice of antiarrhythmic therapy in myocarditis must be individualised based on the patient’s haemodynamic status, underlying myocardial function and the nature of the arrhythmia.⁷⁹ During the acute phase, when inflammation predominates, cautious use of β-blockers and amiodarone is recommended, given their stabilising effects on sympathetic tone and cardiac electrophysiology. In the chronic phase, where fibrosis and structural remodelling dominate, amiodarone remains the mainstay due to its ability to control both ventricular and supraventricular arrhythmias. However, in patients with significant structural damage or ventricular dysfunction, Class IC agents should be avoided, while sotalol may be considered if there is no significant QT prolongation. The potential for arrhythmia with any of these agents warrants close monitoring, especially in myocarditis patients who may experience rapid changes in myocardial substrate and autonomic balance. Regular ECG monitoring and periodic reassessment of ventricular function are essential to optimise therapy and minimise risks.²

Electrical Therapies for Arrhythmia Management in Myocarditis

Device-based strategies play a crucial role in managing the arrhythmic burden associated with myocarditis, especially in patients at high risk of SCD due to VAs or severe conduction abnormalities. The selection of the appropriate device therapy should consider the stage of the disease, the presence of LV dysfunction and the nature of the arrhythmic events. Recent guidelines emphasise a more individualised approach, taking into account the potential for myocardial recovery during the early phases of myocarditis.^7,10,81

ICDs

ICDs are primarily indicated for secondary prevention after a life-threatening VA, such as VT or VF, especially when these events occur beyond the acute inflammatory phase. For patients with persistent LV dysfunction (EF ≤35%) despite optimal medical therapy, ICDs are also indicated for primary prevention of SCD79. The most recent guidelines recommend ICD implantation for primary prevention in patients with chronic myocarditis and significantly reduced EF after at least 3 months of guidelines-directed medical therapy due to the dynamic nature of myocardial recovery.^7,10,81,82

Secondary prevention of SCD mandates ICD implantation in myocarditis patients who have survived cardiac arrest or sustained VT with haemodynamic compromise, particularly if these events occur in the subacute or chronic phase, where the risk of recurrence remains high.⁸³ However, early ICD implantation during the acute phase should be approached cautiously, as arrhythmic events may be transient, especially when the likelihood of myocardial recovery is high, reflecting reversible inflammatory damage rather than persistent structural remodelling.

As outlined in the current guidelines, ICD implantation is recommended (class 1) for patients with cardiomyopathy who have survived a prior cardiac arrest due to VT or VF, or who present with sustained VA associated with syncope or haemodynamic compromise, in the absence of reversible causes. ICD therapy should also be considered (class 2a) in patients with haemodynamically tolerated sustained VT without identifiable reversible factors.^7,82 However, challenges, such as frequent shocks, inappropriate discharges and the risk of arrhythmia storms, are significant.

To mitigate inappropriate therapies, ICD programming should prioritise anti-tachycardia pacing and high-rate cutoffs.⁷⁹ In cases where ICD implantation is deferred during the acute phase, a wearable cardioverter-defibrillator (WCD) can be used to temporarily prevent SCD, allowing both myocardial recovery and more precise risk stratification.^84,85 Their use provides continuous monitoring and protection against SCD during periods in which ventricular dysfunction or electrical instability may be reversible. Beyond immediate arrhythmic protection, WCD facilitates optimisation of medical therapy and follow-up, thereby reducing ICD implant while waiting for cardiac function to recover or arrhythmic burden to cool down. Furthermore, multiparametric remote monitoring offered by WCD can support clinical decision-making and improve patient risk stratification.⁸⁶ However, limitations include patient adherence and uncertainties regarding the optimal duration of use, particularly as the arrhythmic risk may persist beyond the acute phase due to residual myocardial scarring.⁸⁷

CRT

CRT is indicated for myocarditis patients who develop HF with reduced EF (<35%) and electrical dyssynchrony, typically evidenced by left bundle branch block with a QRS duration ≥150 milliseconds. CRT improves ventricular synchronisation, enhancing cardiac output and reducing arrhythmic potential by stabilising electrical conduction. Clinical evidence suggests that CRT reduces mortality and HF hospitalisations in patients with non-ischaemic cardiomyopathy, including chronic myocarditis. The therapy is less effective if the arrhythmogenic substrate is primarily based on diffuse fibrosis rather than mechanical dyssynchrony.⁸⁸ In some cases, CRT may also be appropriate for patients with acute myocarditis who develop persistent ventricular dysfunction, with the aim of preventing progression to irreversible DCM.⁸⁹

Pacemaker

Pacemaker implantation is preferred for myocarditis when there is irreversible high-grade AV block or symptomatic bradycardia that persists beyond the acute inflammatory phase.^2,90 Temporary pacing may suffice during the early phase if AV nodal recovery is anticipated, but in cases where chronic conduction system damage is evident, a permanent pacemaker is warranted.⁸⁸ Maintaining stable AV synchrony through pacing alleviates HF symptoms and reduces the risk of bradycardia-induced arrhythmias. Recent evidence supports the adoption of conduction system pacing, including His bundle pacing and left bundle branch area pacing, as a more physiological pacing modality as opposed to conventional right ventricular stimulation. This approach has demonstrated benefits in both patients with preserved and reduced EF, particularly in those requiring a high pacing percentage, by preserving ventricular synchrony and potentially preventing pacing-induced cardiomyopathy.⁹¹

Catheter Ablation

Catheter ablation may be indicated for patients with myocarditis who experience recurrent VAs despite medical therapy or ICD shocks. Ablation strategies are particularly valuable when the arrhythmic burden significantly impairs quality of life or poses a recurrent life-threatening risk.⁹² Due to the complex arrhythmogenic substrate in myocarditis, which often involves epicardial or mid-myocardial scars, a combined endo-epicardial approach is often required.^93,94 Catheter ablation is generally reserved for the chronic phase after the inflammation has resolved, as performing the procedure during the active phase may result in poor long-term outcomes due to transient arrhythmic foci and evolving substrates.^95,96

Management of myocarditis and VAs comes from correct and timely adoption of diagnostic techniques (Table 2). Before entering an electrophysiology laboratory, transthoracic echocardiography equipped with artificial intelligence can speed up anatomy characterisation; 18F-fluorodeoxyglucose with PET might be useful for the evaluation of myocardial viability and inflammation, although it is not recommended routinely due to lack of clear evidence and large clinical trials. In myocarditis, VT circuits often involve surviving myocytes within fibrotic scars, therefore making 3D electroanatomic mapping crucial for procedural success. Techniques, such as activation mapping, entrainment, and substrate modification targeting late potentials and low-voltage areas, are essential to achieve long-lasting arrhythmic control. Identifying critical isthmuses within the VT circuit reduces recurrent episodes, while complete elimination of local abnormal ventricular activities has been associated with survival free from VT.⁹⁷

In the chronic phase, the substrate responsible for VT is most often represented by re-entrant circuits anchored in viable myocardial fibres interspersed within fibrotic tissue. These circuits are commonly located in subepicardial or mid-myocardial regions, particularly in the inferolateral left ventricular wall.⁹⁸ This anatomical complexity, along with the variable distribution of fibrosis, underscores the importance of a comprehensive approach that integrates both endocardial and epicardial mapping, especially in cases with non-inducible VT or failed prior ablations.⁹⁹

The integration of advanced cardiac imaging further refines patient selection, procedural planning and real-time guidance during ablation. Cardiac MRI with late gadolinium enhancement (Table 2) not only provides detailed scar characterisation – including location, extent and transmurality – but also allows for improved visualisation of conducting channels within areas of fibrosis. These channels, which often serve as critical isthmuses for re-entrant VT circuits, can help guide the operator towards regions of interest.^100,101 Additionally, CT provides high-resolution anatomical detail, particularly useful for delineating the coronary anatomy during epicardial mapping and ablation, as well as for assessing pericardial access feasibility.¹⁰² CT imaging also facilitates the visualisation of epicardial fat, scar morphology and potential intramural channels, and is particularly useful for pre-procedural planning, especially when epicardial access is being considered.^103,104

Among the most advanced functional mapping strategies, isochronal late activation mapping has emerged as a valuable tool. Isochronal late activation mapping identifies zones of decelerated conduction by analysing isochronal crowding, thereby detecting critical isthmuses that support re-entrant VT circuits. This technique enables the operator to focus ablation on key regions that sustain the arrhythmia, enhancing efficacy while minimising unnecessary myocardial injury.¹⁰⁵ Another complementary technique is decrement evoked potential mapping, which adopts extra stimuli to reveal areas characterised by decremental properties – a hallmark of arrhythmogenic, but functionally silent, tissue. Decrement evoked potential mapping is particularly useful for identifying dynamic conduction abnormalities that may not be apparent during baseline mapping.¹⁰⁶

Future Directions

The field of myocarditis management, particularly in relation to arrhythmic burden, is rapidly evolving. The complex interplay of inflammation, structural remodelling, and electrophysiological disruption represents a major diagnostic and therapeutic challenge in myocarditis. While significant progress has been made, future advances are likely to focus on improving risk stratification, personalising therapeutic approaches and incorporating novel technologies to enhance patient outcomes, such as 18F-fluorodeoxyglucose with PET; and advanced tissue characterisation techniques with native T1 and T2 mapping, and extracellular volume quantification allow for more sensitive detection of inflammation and diffuse fibrosis, key contributors to arrhythmogenesis often invisible to standard diagnostic tools.¹⁰⁷

Beyond imaging, the integration of multiomics data (genomics, proteomics, metabolomics) with clinical and imaging variables may unveil mechanistic drivers of arrhythmogenesis and allow for more nuanced patient stratification. For example, genetic variants in ion channels or inflammatory mediators may predispose certain individuals to sustained ventricular arrhythmias, particularly when combined with an inflammatory trigger.

To decode and effectively integrate this multidimensional data, artificial intelligence and machine learning offer the opportunity to build predictive models capable of identifying hidden patterns linked to arrhythmic outcomes. These technologies may synthesise information from electronic health records, imaging datasets, electrophysiological signals and biomarker panels, enabling early identification of high-risk phenotypes and guiding therapeutic decision-making (Figure 1 ). Predictive models could help identify subtle patterns that correlate with arrhythmic outcomes, enabling more precise patient monitoring and tailored therapeutic interventions.¹⁰⁸

Therapeutic innovation should follow the same logic of personalisation. For instance, targeting specific inflammatory pathways, such as IL-1 or TNF-α, during the acute phase may attenuate the transition to chronic structural remodelling.¹⁰⁹ Early evidence from ongoing trials with biologic agents supports this hypothesis, although their impact on rhythm outcomes warrants targeted investigation in future studies.¹¹⁰

Conclusion

The integration of imaging, molecular and computational tools rather than just a technological enhancement represents a paradigm shift towards a mechanism-based, patient-tailored workflow to managing arrhythmias in myocarditis. This approach will allow clinicians to detect and treat arrhythmias more effectively, and on the other hand, to predict, prevent and personalise interventions with greater precision.