Viral Myocarditis🦠🫀📚

Introduction 📘🧠🫀

✔️ Myocarditis is a relatively common but potentially life-threatening 🛑 inflammatory disease of the myocardium 🫀, defined through histological, immunological, and immunohistochemical criteria.

✔️ It affects millions 🌍, particularly children and young adult males 🧍♂️, and is a leading cause of sudden cardiac death (SCD) 🚨, initially unexplained dilated cardiomyopathy (DCM) 🫀, and heart failure (HF) in these groups.

✔️ While endomyocardial biopsy (EMB) is the diagnostic gold standard 📋, it's underutilized in clinical practice. Most diagnoses rely on clinical presentation, biomarkers 🧪, and imaging findings.

✔️ Cardiac Magnetic Resonance (CMR) imaging has emerged as the non-invasive reference technique 🖥️ for diagnosis and follow-up of myocarditis patients, thanks to: 👉 Excellent evaluation of cardiac structure 👉 Non-invasive tissue characterization 👉 No ionizing radiation ☢️

✔️ CMR aids in diagnosis, subclinical case detection, risk stratification based on independent prognostic factors (e.g., LVEF, end-systolic volume, extent of myocardial edema), prognosis prediction, and therapy monitoring ⏳.

✅ Today lets explore current overview on:

🫵 Classification

🫵 Clinical impact

🫵 Treatment

🫵 Imaging in diagnosis and prognosis

🫵 Arrhythmias in myocarditis: prevalence, mechanisms, prognosis, and treatment ⚡

Classification 🏷️🧪🧬

✔️ Myocarditis is polymorphic and complex — multiple classification strategies exist: 👉 By cell type at EMB:

• Lymphocytic
• Eosinophilic
• Giant cell or granulomatous myocarditis 👉 By etiopathogenic mechanism:
• Infectious vs. Non-infectious

✔️ Non-infectious forms include:

👉 Toxic myocarditis (from drugs, toxins, physical agents)

👉 Immune-mediated myocarditis, due to allergens, alloantigens, or autoantigens (e.g., in systemic autoimmune disease or giant cell myocarditis)

✔️ Infectious myocarditis may result from various pathogens, with regional variations in etiology 🌍:

👉 In resource-limited areas: rheumatic disease, Chagas disease, HIV, helminthic or bacterial infections

👉 In Western countries: viral etiologies predominate

Pathogenesis 🧬🦠🫀

Acute Infectious Phase (1–7 days) ⏳🧫

✔️ Triggered by viral entry ➡️ cardiomyocyte death

✔️ Immune activation via exposed host proteins

✔️ Examples:

👉 Adenovirus & Enterovirus — cytolytic, use CAR receptor, cleave dystrophin

👉 Parvovirus B19 — infects endothelium, induces cytokines

👉 Influenza viruses — molecular mimicry triggers autoimmunity

✔️ Involves neutrophils, NK cells, macrophages, dendritic cells

Subacute Immune Phase (1–4 weeks) ⏳⚔️

✔️ Dominated by adaptive T-cell response

👉 CD4+ and CD8+ cells show dual effects

👉 B-cell role remains unclear

Recovery or Chronic Myopathic Phase 🕊️➡️📉

✔️ Pathogen clearance restores function

✔️ Genetic susceptibility

➡️ chronic inflammation, DCM, end-stage HF

✔️ Th17 cells promote fibrosis (IL-17-deficient mice had less fibrosis)

✔️ Tregs (↓ in myocarditis) are vital for tolerance

COVID-19 and Myocarditis 🦠🫀🧬

✔️ Multiple case reports describe suspected myocarditis in patients with COVID-19, including fulminant forms 🚨.

✔️ Cardiac injury (elevated troponins) has been observed in 19–28% of COVID-19 patients and is linked to worse outcomes 📉.

✔️ However, the exact epidemiology is difficult to ascertain due to potential confounders like chronic coronary syndromes 🧪.

🧠 Key Findings from Large Studies:

✅ A retrospective global cohort: Among 718,365 COVID-19 patients, 5% developed new-onset myocarditis. Mortality at 6 months: 3.9%.

✅ A U.S. administrative database: Patients with COVID-19 were 16× more likely to develop myocarditis vs. non-COVID patients.

✅ Myocarditis hospital encounters rose by 42.3% in 2020 (from 3,205 in 2019 to 4,560 in 2020). Peaks in myocarditis aligned with COVID-19 waves ⏳.

🧪 Multinational database analysis:

✔️ All-cause 30-day mortality in propensity-matched COVID-19 cohorts: 🫵 With myocarditis: 13.4% 🫵 Without myocarditis: 4.2%

Pathogenesis Theories:

✔️ Direct myocardial entry via ACE2 receptors 🧬

✔️ Hyperimmune/inflammatory response (cytokine storm) ⚠️

Systematic Review Data (n = 38):

✔️ CMR was used in 25 cases

✔️ EMB confirmed myocarditis in 12 cases (8 biopsies, 4 autopsies)

✔️ SARS-CoV-2 genome detected in 5/104 EMBs — supporting cardiotropism 🧫

Long-term Concerns:

✔️ In a German cohort of recovered COVID-19 patients:

🫵 CMR showed cardiac involvement in 78%

🫵 Ongoing myocardial inflammation in 60% — regardless of symptoms, preconditions, or illness severity

Vaccine-Associated Myocarditis 💉⚠️

✔️ Rare but recognized, mostly post-mRNA vaccination (especially after dose 2)

✔️ Three proposed mechanisms: 👉 mRNA immune reactivity 👉 Spike protein cross-reactivity 👉 Testosterone-linked aggressive Th1 response in males

✔️ Incidence: 3–5 cases per 100,000 vaccinated (U.S. & Israel)

✔️ Risk with COVID-19 infection: 1,000–1,400 per 100,000 — 100× higher than with vaccines

✔️ Clinical course: usually mild, self-limiting ☑️

Clinical Presentation 🧍♂️📋🩺

✔️ Commonly affects young adult males

✔️ Clinical spectrum ranges from subclinical to sudden cardiac death (SCD) ⚠️

✔️ Reflects heterogeneity in histology, etiology, and disease stage

Most Common Symptoms:

✔️ Chest pain (up to 95%)

✔️ Dyspnea (up to 49%)

✔️ Fatigue, palpitations, syncope

✔️ Fever or GI prodrome in 18–80%

Temporal Classifications (ESC & literature):

✔️ Acute: ≤3 months

✔️ Subacute: 1–3 months

✔️ Chronic: >3 months

ESC's Three Acute Profiles:

✅ ACS-like: chest pain, ST/T changes, LV/RV dysfunction, elevated troponin

✅ New or worsening HF: LV/RV dysfunction, AV/IV blocks, arrhythmias

✅ Fulminant myocarditis: severe dysfunction, shock, need for inotropes or mechanical support

✔️ Fulminant forms more frequent in children and women

🧪 Multicenter Italian registry (n=443):

✔️ 26.6% had complicated myocarditis

✔️ These patients had higher risk of cardiac death or heart transplant at 5 years

✔️ Chronic cases may present late with stable HF symptoms >3 months

✔️ Troponin may be mildly elevated despite severe LV dysfunction

✔️ Imaging or EMB often needed for definitive diagnosis

Diagnosis 🧪🔬🖥️

Transthoracic Echocardiography (TTE):

✔️ First-line, especially in unstable patients

✔️ Helps rule out other HF or chest pain causes

✔️ Common findings:

👉 Regional wall motion abnormalities (inferior/inferolateral)

👉 Diastolic dysfunction

👉 Global LV dysfunction

👉 Fulminant: thickened, echogenic LV with RV dysfunction

👉 Normal volumes help distinguish acute vs chronic inflammatory cardiomyopathy

Advanced Echo Techniques:

✔️ 2D Speckle tracking echocardiography: Prognostic in suspected myocarditis with preserved EF

✔️ 2015 study: Correlation between strain and CMR-detected edema

✔️ RTMCE: May show perfusion delay due to microvascular issues (limited data)

Nuclear Imaging:

✔️ Not routinely recommended due to low sensitivity

✔️ Indium-111 antimyosin scintigraphy: shows necrotic areas

✔️ 18F-FDG PET: may help in sarcoidosis or CMR contraindications

CT Imaging:

✔️ MDCT & DE-MDCT can differentiate ischemic vs non-ischemic cardiomyopathy

Cardiac Magnetic Resonance (CMR) in Diagnosis 🖥️🫀🔍

✔️ CMR has become the non-invasive gold standard for diagnosis and follow-up in myocarditis 📊.

✔️ Advantages include:

👉 High reproducibility for structural evaluation

👉 Tissue characterization without ionizing radiation

👉 Multipurpose: diagnosis, subclinical screening, risk stratification, prognosis, and therapy monitoring ⏳

Lake Louise Criteria (LLC) 📝📚

✔️ Original 2009 Criteria:

👉 Edema: high T2-weighted signal

👉 Hyperemia: early gadolinium enhancement (EGE)

👉 Necrosis/Fibrosis: late gadolinium enhancement (LGE)

✅ Diagnosis if 2 of 3 criteria present (Sensitivity: 74%, Specificity: 86%)

✔️ Many myocarditis cases present with preserved LVEF, emphasizing the role of tissue characterization 🧬

LGE Patterns in Myocarditis 🧠🩻

✔️ Patchy, non-contiguous subepicardial LGE — often in the LV free wall

✔️ Septal mid-wall lesions are typical

✔️ Differentiates from ischemic causes (which have subendocardial LGE)

✔️ Italian multicenter study:

👉 Most frequent LGE: inferolateral subepicardial

👉 Mid-septal LGE common in HF/arrhythmic presentations

👉 Larger LV volumes, lower EF, and RV dysfunction more frequent in these patterns

Prognostic Role of LGE 📉📈

✔️ LGE extent and location are strong outcome predictors

✔️ New tools like T1/T2 mapping and extracellular volume quantification have emerged

T1 & T2 Mapping Techniques 📊🧬

✔️ T1 Mapping: Pixel intensity reflects T1 relaxation time

👉 Detects early diffuse fibrosis not visible on LGE

👉 Safe in renal insufficiency, heart-rate independent

⚠️ Limitations: lack of standardization due to emerging nature

✔️ T2 Mapping: Quantifies T2 relaxation times — visualizes edema

✔️ Updated LLC 2018:

✅ Diagnostic if both:

👉 T1-based: increased native T1, extracellular volume, or LGE

👉 T2-based: increased T2 signal or T2-mapping

⚠️ Presence of one criterion can still support diagnosis but is less specific

✔️ New LLC shows:

👉 Sensitivity: 87.5%

👉 Specificity: 96.2%

✔️ Mapping may also detect tissue changes in subacute/chronic stages when T1/T2-weighted images lack sensitivity

Management of Myocarditis 🏥🛠️🫀

✔️ Treatment mainly involves non-specific strategies based on expert consensus due to lack of large RCTs 📉

✔️ Focus: Viral-induced myocarditis — other subtypes like eosinophilic/giant cell are not covered

General Management Principles 🧾

✔️ Even stable or mildly symptomatic patients should be hospitalized 🏥 for monitoring due to arrhythmic risk

✔️ Concerning signs: 👉 Persistent troponin elevation 👉 Bradycardia 👉 Prolonged QRS 👉 Progressive motion abnormalities on echo

✔️ Coronary angiography or CT angiogram may be needed to rule out ACS in chest pain with ischemic changes

✔️ HF management: Follow HF guidelines

✔️ Uncertainty exists regarding weaning therapy post-LV recovery

✔️ Beta-blockers: Commonly used for perceived anti-arrhythmic benefit ⚠️ NSAIDs (esp. aspirin): Not recommended 👉 Despite use in pericarditis, linked to increased mortality in experimental myocarditis models

Activity Restriction 🚴🛑

✔️ Strict rest advised in acute phase to reduce SCD risk

✔️ No exercise testing during acute phase

✔️ Athletes: Avoid competition for 3 months minimum

✔️ Re-evaluation required before return to sport

Antiviral and Immunosuppressive Treatments 💉🧪🧫

✔️ No specific evidence-based antiviral therapy for viral myocarditis to date

Experimental Therapies:

✔️ Interferon-β: May aid viral clearance in enterovirus/adenovirus cases and improve outcomes — needs more data

✔️ Antivirals (acyclovir, ganciclovir, valacyclovir): Used in fulminant herpes infections — unclear myocarditis-specific benefits

Parvovirus B19 (B19V) Therapies under Study:

✅ High-dose IVIG

✅ Telbivudine (nucleoside analog)

✅ Prednisone + Azathioprine (immunosuppressants)

✔️ IVIG: Anti-inflammatory and antiviral properties

✅ Pediatric studies: improved LV recovery and 1-year survival

✅ One adult RCT: LV function improved + increased anti-inflammatory cytokines

❌ Other studies: No benefit in LVEF recovery

✔️ Immunoadsorption: Shows promise in small RCTs — ↓ inflammation, improved LV function in idiopathic DCM

✔️ Immunosuppressive therapy: Recommended only in virus-negative cases, per current guidelines ⚠️ May be future strategy for virus-positive cases (e.g., B19V)

Temporary Circulatory Support 💓🛠️🏥

✔️ Acute myocarditis can cause rapid decompensation, leading to cardiogenic shock 🚨 due to decreased cardiac output.

✔️ Initial therapy:

✅ Mechanical ventilation to reduce O₂ demand

✅ Inotropes/vasopressors to maintain perfusion and contractility

⚠️ High-dose vasoactives can increase oxygen consumption without improving outcome — mechanical support often required.

Mechanical Circulatory Support Options 🩺🖥️

✔️ Intra-aortic balloon pump

✔️ Veno-arterial ECMO (VA-ECMO) — rapid, supports both ventricles

✔️ Impella — can be combined with ECMO for LV unloading and early weaning

🧠 Early mechanical support:

✅ Improves hemodynamics

✅ Reduces systemic inflammation

✅ May guide VAD or transplant candidacy

✔️ No evidence favors one support system over another yet

Arrhythmias in Myocarditis ⚡🫀🚨

✔️ A major clinical entity within myocarditis is “arrhythmic myocarditis” — underrecognized and underreported ⚠️

✔️ Can occur in acute "hot" phase or chronic "cold" phase — wide spectrum from benign to fatal

Prevalence:

🧠 First presentation with arrhythmia/syncope/SCD in 24% of cases

🧪 Non-sustained VT: 28%

🧪 Sustained VT or VF: 7.3–9.7%

🧪 AF: 2.5–14%

🧪 Other SVTs: <1%

🧪 AV block: 1.7–10% ⚠️ Female gender = risk for AV block; advanced AV block = ↑ morbidity/mortality

✔️ Myocarditis implicated in SCD in:

✅ 2% of infants

✅ 5% of children

✅ 4–8% of athletes

✔️ Non-lymphocytic myocarditis (e.g., giant cell, sarcoidosis) = higher arrhythmic risk

✅ GCM: VT in 29%

✅ CS: VT in 55%

✅ Myopericarditis: fewer arrhythmias (<10%)

✔️ HIV-related myocarditis = more arrhythmias than other viral causes

✔️ Athletes with myocarditis are high-risk for VT and SCD

🧬 Intense training may:

✅ Lower immunity

✅ Promote viral virulence (e.g., Coxsackievirus B3 in mice)

✅ Increase necrosis and mortality

✅ Myocarditis = 10% of athlete SCDs

Mechanisms of Arrhythmia in Myocarditis 🔬⚡🧠

Acute "Hot" Phase:

☑️ Direct viral cytolysis = electrical instability

☑️ Cytokine-mediated edema = automaticity

☑️ Gap junction dysfunction (e.g., Coxsackievirus B3)

☑️ Microvascular ischemia (e.g., Parvovirus B19)

☑️ Altered calcium handling

☑️ Ion channelopathy — ↓ Kv4.2 potassium channels

☑️ Genetic arrhythmogenic cardiomyopathy (AC) may mimic or be unmasked by myocarditis

Chronic "Cold" Phase:

☑️ Scar-mediated reentry from subepicardial/mid-wall fibrosis (“band” pattern)

☑️ Electrical remodeling without ongoing necrosis 🧠 Peretto et al.:

✅ Acute = polymorphic arrhythmias

✅ Chronic = monomorphic arrhythmias

✔️ French study:

✅ VF = most common arrhythmia in acute phase (58%)

✅ VT = most common in chronic phase (78%)

✅ Arrest: 68% acute vs 30% chronic

Short-Term Prognosis & Treatment of Arrhythmic Myocarditis 🩺📉💊

✔️ Non-sustained VT, PACs, PVCs = benign if asymptomatic — no treatment

✔️ Symptomatic VT = treat with:

✅ Beta-blockers

✅ Amiodarone or Mexiletine

✔️ Refractory life-threatening arrhythmias = poor prognosis ⚠️

✅ ↑ need for mechanical support, transplant, or risk of SCD

✔️ Pediatrics:

✅ Tachyarrhythmias → 2.3× ↑ mortality

✅ 58% ↑ hospital stay

✅ 28% ↑ cost/day

Endomyocardial Biopsy (EMB) Role:

🧬 Required for:

✅ Arrhythmias with hemodynamic instability

✅ Helps define:

☑️ Etiology

☑️ Acute vs chronic

☑️ Virus-positive vs negative

☑️ Active viral vs latent infection (e.g., B19V DNA vs RNA)

✔️ Recommended if:

✅ Severe HF

✅ Shock

✅ High-grade AV block

✅ Immune checkpoint inhibitor-associated myocarditis

✅ Persistent biomarkers

✔️ Best results if performed:

✅ Within 2 weeks of onset

✅ With 4–6 specimens

Long-Term Prognosis & ICD Indications in Arrhythmic Myocarditis ⏳🫀⚡

✔️ Acute-phase arrhythmias often resolve but may recur, challenging the view of myocarditis as fully reversible ⚠️

✔️ European guidelines: Delay ICD until resolution of acute phase ❗Recent data contradict this — early ICD may be lifesaving even after LVEF recovery

Key Studies and Findings 📊:

✔️ Lombardy Registry:

✅ Patients with complex ventricular arrhythmias had worse long-term outcomes

✅ Uncomplicated cases had low risk of future arrhythmias or LV dysfunction

✔️ French Study:

✅ VT/VF in acute phase

➡️ 39% had recurrence of major ventricular arrhythmias (MAEs)

✅ 80% of those declining ICD had recurrent events

✅ 82% of first MAEs occurred after 3 months — post-WCD period ⚠️ Challenges WCD’s utility if used only for 3 months

✔️ Italian Study:

✅ 54% with secondary-prevention ICDs had MAEs in follow-up (~65 months)

S-ICD vs. TV-ICD in Young Patients 🧍♂️🔋

✔️ S-ICD preferred when pacing not needed

✅ Fewer lead/generator complications

✅ Safe and effective even in teens

Primary Prevention Strategy 🛡️

✔️ Acute myocarditis + LVEF ≤35% but no MAEs:

✅ Consider WCD as bridge during therapy optimization

✅ Consider early ICD (new suggestion based on evolving evidence)

✔️ Chronic inflammatory cardiomyopathy + LVEF ≤35%:

✅ Follow standard HF guidelines for ICD implantation

✅ 30% may need ICD/CRT-D

✅ 50% of those had at least one MAE

Secondary Prevention Strategy 🛑⚡

✔️ MAE in acute myocarditis:

✅ Implant ICD before discharge

❌ Do not rely solely on WCD for 3 months

✔️ MAE in chronic phase:

✅ ICD implantation mandatory

Predictors of Arrhythmias in Myocarditis from Imaging 🖥️📊🫀

Echocardiographic Parameters:

✔️ LVEF is a basic tool — but many have preserved LVEF

✔️ Global longitudinal strain (GLS) is a stronger predictor:

✅ GLS ≥12%

➡️ predicts non-sustained VT

✅ GLS ↓ in those with arrhythmias, HF, or shock

CMR Parameters:

✔️ Late Gadolinium Enhancement (LGE):

✅ Strong predictor of:

🫵 All-cause death

🫵 Cardiac death

🫵 SCD

🫵 HF hospitalization

🫵 Recurrent myocarditis

🫵 Sustained VT

✔️ Location & pattern matter:

✅ Septal, mid-wall LGE = highest risk

✅ Patchy = 3× higher MACE risk

✅ LGE extent (per 10%) = 79% ↑ in MACE risk

✔️ ITAMY Registry (n=374, normal EF):

✅ LGE (esp. mid-wall anteroseptal) = ↑ risk of: 🫵 HF hospitalizations 🫵 SCD 🫵 ICD shocks

✔️ Follow-up CMR after 6 months:

✅ LGE + no edema = fibrosis ➡️ poor prognosis

✅ LGE + edema = active inflammation ➡️ possible recovery

Meta-Analysis Findings:

✔️ LGE presence = 3× risk of MACE over 2 years ✔️ Extensive LGE or anteroseptal location = doubled risk

CMR Strain Analysis (Feature Tracking):

✔️ Predicts:

🫵 Cardiac death

🫵 ICD use

🫵 Stroke

🫵 HF hospitalization

✔️ GLS = independent of EF and LGE

The Bottom Line ✅🫀⚠️

🎯 Myocarditis is a diverse, deadly, and dynamic disease.

Reference📖

Sozzi FB, Gherbesi E, Faggiano A, Gnan E, Maruccio A, Schiavone M, Iacuzio L, Carugo S. Viral Myocarditis: Classification, Diagnosis, and Clinical Implications. Front Cardiovasc Med. 2022;9:908663. doi:10.3389/fcvm.2022.908663.

Further Reading 📚

• Caforio ALP, Pankuweit S, Arbustini E, Basso C, Gimeno-Blanes J, Felix SB, et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur Heart J. 2013;34(33):2636–2648. doi:10.1093/eurheartj/eht210.
• Tschöpe C, Ammirati E, Bozkurt B, Caforio ALP, Cooper LT, Felix SB, et al. Myocarditis and inflammatory cardiomyopathy: current evidence and future directions. Nat Rev Cardiol. 2021;18(3):169–193. doi:10.1038/s41569-020-00435-x.
• Kühl U, Pauschinger M, Noutsias M, Seeberg B, Bock T, Lassner D, et al. High prevalence of viral genomes and multiple viral infections in the myocardium of adults with "idiopathic" left ventricular dysfunction. Circulation. 2005;111(7):887–893. doi:10.1161/01.CIR.0000155616.07901.35.