Myocarditis (Viral & Toxic)

1. Introduction

• Myocarditis is a diagnostic chameleon mimicking ischemia, arrhythmias, cardiomyopathy.
• Requires mechanistic understanding beyond viral associations.
• Centers on myocardial inflammation, immune phases, hemodynamic consequences.
• Integrates 2024 ACC Expert Consensus Decision Pathway principles.
• Anchored in Fourth Universal Definition of Myocardial Infarction.
• Emphasizes pathophysiology-driven diagnostic and therapeutic reasoning.
• Highlights advanced imaging and immunosuppression indications.
• Designed for high-acuity clinical decision-making and revision.

I. Conceptual Framework & Definitions

1. The Fourth Universal Definition of Myocardial Infarction: Injury vs. Infarction

Myocardial Injury

• Defined as cardiac troponin elevation above 99th percentile upper reference limit.

$99^{th}\ \text{percentile upper reference limit}$

• Represents laboratory finding, not a clinical diagnosis.
• Reflects cardiomyocyte membrane disruption with protein leakage.
• Occurs via ischemic or non-ischemic mechanisms.
• Ischemic mechanisms
• Plaque rupture.
• Supply–demand mismatch.
• Non-ischemic mechanisms
• Inflammation (myocarditis).
• Direct toxicity (anthracyclines).
• Trauma (contusion).
• Wall stress (acute heart failure).

Myocarditis as Non-Ischemic Injury

• Myocardial infarction requires injury plus ischemic evidence.
• Ischemic evidence includes symptoms, ECG, Q waves, imaging changes.
• Myocarditis lacks ischemic mechanism despite troponin elevation.
• Normal coronary arteries strongly suggest myocarditis.
• Myocarditis is non-ischemic myocardial injury, not Type 2 MI.
• Type 2 MI requires independent supply–demand ischemia.

2. The 2024 ACC Expert Consensus Staging System

Stage A: At-Risk for Myocarditis

• Exposure to triggers without symptoms or myocardial injury.
• Includes recent viral illness or cardiotoxic therapy exposure.
• Examples include SARS-CoV-2, influenza, anthracyclines, ICIs.
• Management emphasizes surveillance and patient education.
• Baseline echocardiography and biomarkers recommended in oncology.

Stage B: Pre-Symptomatic Myocarditis

• Subclinical myocardial injury or dysfunction without symptoms.
• Evidence includes biomarker elevation, GLS reduction, LGE on CMR.
• Often detected during routine monitoring.
• Critical for early intervention in cardio-oncology.
• Allows drug withholding before fulminant myocarditis.

Stage C: Symptomatic Myocarditis

• Symptoms include chest pain, dyspnea, palpitations, fatigue.
• Objective evidence of myocardial inflammation present.
• Represents classic acute myocarditis presentation.
• Often follows viral prodrome in young adults.

Stage D: Complicated/Fulminant Myocarditis

• Symptomatic myocarditis with hemodynamic or electrical instability.
• Includes cardiogenic shock or sustained ventricular arrhythmias.
• Requires inotropes, vasopressors, or mechanical support.
• Rapid deterioration in previously healthy individuals.
• Often lymphocytic or giant cell subtype.

II. Pathophysiology & Immunopathogenesis

1. The Tri-Phasic Model of Viral Myocarditis

Phase 1: Viral / Acute Phase (Days 0–7)

• Direct viral cytotoxicity causes cardiomyocyte injury.
• Viruses enter via Coxsackie–Adenovirus receptor.
• Viral replication hijacks host cellular machinery.
• Protease 2A cleaves dystrophin causing cytoskeletal failure.
• Innate immune activation via Toll-like receptors.
• Cytokines include IL-1β, TNF-α, IFN-γ.
• Corresponds to systemic prodromal symptoms.
• Immunosuppression contraindicated due to viral replication risk.

Phase 2: Autoimmune / Subacute Phase (Weeks 1–4)

• Adaptive immune activation persists after viral clearance.
• Molecular mimicry targets cardiac myosin heavy chain.
• CD4+ and CD8+ T-cells cross-react with myocardium.
• Epitope spreading exposes cryptic intracellular antigens.
• Ongoing immune-mediated myocardial injury.
• Presents with heart failure or arrhythmias.
• Histology shows lymphocytes with myocyte necrosis.
• Dallas criteria have low sensitivity (≈10–20%).
• Modern diagnosis uses immunohistochemistry and viral PCR.

Phase 3: Chronic / Remodeling Phase (Months–Years)

• Persistent inflammation or maladaptive repair.
• Approximately 30% progress to chronic disease.
• TGF-β stimulates fibroblast-driven fibrosis.
• Ventricular dilation compensates for contractile loss.
• Leads to systolic dysfunction and heart failure.
• Progression to dilated cardiomyopathy common.

2. Mechanisms of Toxic Myocarditis

Anthracyclines

• Traditional mechanism involves iron-mediated oxidative stress.
• Primary mechanism is Topoisomerase IIβ inhibition.
• Drug–DNA–Top2β complex causes double-strand breaks.
• Activates p53-mediated apoptosis.
• Induces mitochondrial dysfunction and cell death.
• Injury is cumulative and dose-dependent.

Immune Checkpoint Inhibitors

• Block PD-1/PD-L1 or CTLA-4 immune checkpoints.
• Remove inhibitory signals on cytotoxic T-cells.
• Myocardial PD-L1 normally limits autoimmunity.
• Disinhibition enables T-cell myocardial infiltration.
• Causes fulminant necrotizing lymphocytic myocarditis.
• Mortality reduced from 40–50% to ~15–25%.

Cocaine

• Multifactorial myocardial toxicity.
• Sympathomimetic excess causes coronary vasospasm.
• Results in severe ischemic supply–demand mismatch.
• Sodium channel blockade depresses contractility.
• Generates oxidative stress and arrhythmogenicity.

III. Clinical Presentation & Vignette Profiles

1. Pseudo-Ischemic Presentation

• Young patient (<40 years) with acute chest pain.
• Pain may be pleuritic or angina-like.
• ECG shows diffuse or atypical ST elevation.
• Troponin elevated with normal coronary arteries.
• Caused by subepicardial inflammation and myopericarditis.
• Distinguished from STEMI by ECG pattern and demographics.

2. Arrhythmic Presentation

• Presents with syncope, palpitations, or sudden cardiac arrest.
• No preceding heart failure symptoms.
• ECG shows VT, AV block, or bundle branch block.
• Giant cell myocarditis causes electrical storm.
• Sarcoidosis causes AV block and VT.
• Lyme carditis causes fluctuating AV block.

3. Fulminant Failure Presentation

• Rapid onset severe dyspnea and fatigue.
• Signs of cardiogenic shock present.
• Echocardiogram shows severe systolic dysfunction.
• LV cavity normal or reduced with wall thickening.
• Represents diffuse myocardial necrosis.
• Survivors often recover with favorable long-term prognosis.

IV. Diagnostic Evaluation

1. Electrocardiography

• Abnormal in approximately 50–90% of cases.
• Normal ECG does not exclude myocarditis.
• Diffuse concave ST elevation suggests myopericarditis.
• PR depression indicates pericardial involvement.
• AV block suggests Lyme, sarcoid, giant cell, diphtheria.
• QRS widening indicates poor prognosis.
• Pseudo-infarct Q waves may be transient.

2. Biomarkers

Cardiac Troponin

• High-sensitivity troponin detects myocardial injury.
• Sensitivity exceeds 80%.
• Normal values do not exclude chronic disease.
• Elevation may persist for weeks.
• Kinetic patterns are variable and may mimic acute myocardial infarction.

Acute Phase Reactants

• ESR and CRP often elevated.
• Non-specific but useful for autoimmune disease monitoring.

Natriuretic Peptides

• Reflect ventricular wall stress.
• Correlate with dysfunction severity.
• Predict heart failure progression.

3. Echocardiography

• First-line imaging for functional assessment.
• Wall motion abnormalities are global or patchy.
• Pseudohypertrophy from edema may occur.
• Pericardial effusion is common.
• Intracavitary thrombus may be present.

4. Cardiac Magnetic Resonance

• Gold standard non-invasive diagnostic modality.
• Enables myocardial tissue characterization.

Updated Lake Louise Criteria

• Requires edema and non-ischemic injury evidence.

• Myocarditis shows subepicardial or mid-wall LGE.
• Ischemia shows subendocardial or transmural LGE.
• LGE predicts adverse outcomes.

5. Endomyocardial Biopsy

• Definitive diagnostic gold standard.
• Limited by invasiveness and sampling error.
• Reserved for management-altering scenarios.

Indications

1. New-onset heart failure <2 weeks with instability.
2. Heart failure 2 weeks–3 months with arrhythmias or AV block.
3. Suspected immune checkpoint inhibitor myocarditis.
4. Suspected eosinophilic myocarditis.

V. Etiology-Specific High-Yield Modules

1. Viral Myocarditis

• Coxsackievirus B causes direct cytolysis.
• Parvovirus B19 targets endothelial cells.
• SARS-CoV-2 causes direct myocarditis or MIS-A.

2. Bacterial Myocarditis

• Lyme disease causes fluctuating AV block.
• Diphtheria causes toxin-mediated conduction failure.

3. Parasitic Myocarditis

• Chagas disease causes apical aneurysm and conduction disease.

4. Toxic & Drug-Induced Myocarditis

• ICIs cause immune-mediated myocardial destruction.
• Anthracyclines cause cumulative DNA damage.
• Cocaine causes vasospasm and arrhythmias.

5. Autoimmune Myocarditis

• Giant cell myocarditis causes fulminant HF and VT.
• Cardiac sarcoidosis causes AV block and VT.

VI. Differential Diagnosis

VII. Management & Therapeutics

1. Hemodynamic Support

• Stable patients receive GDMT.
• Beta-blockers after euvolemia.
• RAAS inhibition prevents remodeling.
• MRAs provide antifibrotic benefit.
• SGLT2 inhibitors included.
• Shock requires inotropes and vasopressors.
• Early mechanical support improves survival.

2. Mechanical Circulatory Support

• Used as bridge to recovery.
• Impella unloads left ventricle.
• VA-ECMO supports heart and lungs.
• Survival to discharge ~60–70%.

3. Immunosuppression Strategy

• Avoid steroids in acute viral myocarditis.
• Mandatory in giant cell, sarcoid, eosinophilic, ICI myocarditis.
• Selective use in virus-negative chronic inflammatory cardiomyopathy.

4. Activity Restriction

• Strict abstinence for 3–6 months.
• Exercise may exacerbate inflammation and arrhythmic risk.
• Return requires recovered EF, normal biomarkers, no arrhythmias.

VIII. Prognosis & Follow-Up

1. Progression to Dilated Cardiomyopathy

• Occurs in approximately 30% of cases.
• Driven by persistent immune-mediated injury.

2. Predictors of Poor Outcome

• Syncope and conduction disease.
• Fulminant presentation.
• Presence of LGE on CMR.
• Giant cell or eosinophilic histology.

3. Follow-Up Imaging

• Stage C/D: echo at 2–4 weeks.
• Six-month reassessment with echo or CMR based on risk.

IX. Memory Anchors & Mnemonics

1. Lyme hurts the line → AV block.
2. Chagas causes sagging apex → apical aneurysm.
3. Giant cell equals giant storm → VT storm.
4. Lake Louise is wet and scarred → edema and fibrosis.

X. Quick-Recap: High-Yield Associations