Myocarditis

Topic Overview

Summary

Myocarditis is inflammation of the myocardium with a heterogeneous spectrum of clinical presentations ranging from subclinical disease to fulminant heart failure and sudden cardiac death. The condition is most commonly caused by viral infections, though autoimmune disorders, toxins, and drugs are increasingly recognized etiologies. Clinical presentation varies from mild chest discomfort to acute heart failure, life-threatening arrhythmias, or cardiogenic shock. [1]

The diagnosis requires high clinical suspicion, particularly in young patients presenting with cardiac symptoms following viral illness. Cardiac magnetic resonance imaging (CMR) has emerged as the gold standard non-invasive diagnostic tool, using the Lake Louise criteria to identify myocardial inflammation and injury. [2,3] Endomyocardial biopsy remains the histological gold standard but is reserved for specific clinical scenarios due to its invasive nature and sampling error limitations. [4]

Management is primarily supportive, focusing on heart failure treatment and arrhythmia control. Immunosuppressive therapy is reserved for specific histological subtypes such as giant cell myocarditis and cardiac sarcoidosis. [5] Prognosis is variable: most patients recover completely, but 10-25% progress to dilated cardiomyopathy requiring long-term management or transplantation. [6,7] Paradoxically, fulminant myocarditis—despite its acute severity—has better long-term outcomes than acute non-fulminant disease if patients survive the initial presentation. [8]

Key Facts

• Incidence: 22 per 100,000 person-years (likely underestimated due to subclinical cases) [9]
• Causes: Viral (60-70%), autoimmune (15-20%), drug-induced (5-10%), idiopathic (15-20%) [1,10]
• Peak Age: Bimodal—young adults (20-40 years) and infants
• Male Predominance: Male-to-female ratio approximately 1.5-1.7:1 [11]
• Presentation Triad: Chest pain + heart failure symptoms + arrhythmias (classic but not always complete)
• ECG Findings: Diffuse ST elevation (40-50%), PR depression, T wave inversion, arrhythmias [12]
• Troponin: Elevated in 50-75% of cases [13]
• CMR Sensitivity: 75-85% using updated Lake Louise criteria [2,3]
• Mortality: 1-7% in-hospital; fulminant myocarditis 40-50% without mechanical support [8,14]
• Long-term DCM: 10-25% develop dilated cardiomyopathy [6,7]

Clinical Pearls

Young patient with chest pain + elevated troponin + recent viral illness = myocarditis until proven otherwise. Do NOT assume acute coronary syndrome without considering this diagnosis.

ECG in myocarditis shows diffuse (not regional) ST elevation without reciprocal changes—unlike STEMI which shows regional changes with reciprocal ST depression.

Cardiac MRI is the non-invasive gold standard. The updated Lake Louise criteria require both T1-based and T2-based abnormalities for diagnosis. [2,3]

Fulminant myocarditis presents with cardiogenic shock but has BETTER long-term prognosis than acute non-fulminant disease if the patient survives the acute phase. [8]

Avoid NSAIDs in acute myocarditis—animal studies suggest increased mortality and myocardial damage, though human data is limited. [15]

Activity restriction for 3-6 months is critical—return to competitive sport has been associated with sudden cardiac death during the inflammatory phase. [16]

Why This Matters Clinically

Myocarditis represents a critical diagnostic challenge with significant implications:

1. Diagnostic Mimicry: Can present identically to acute MI, leading to unnecessary coronary intervention or missed diagnoses
2. Sudden Death Risk: Leading cause of sudden cardiac death in young athletes and military recruits [17]
3. Long-term Sequelae: Major cause of "idiopathic" dilated cardiomyopathy and heart transplantation in younger patients [18]
4. Public Health: Increasing recognition of vaccine-associated myocarditis (particularly mRNA COVID-19 vaccines) requires balanced risk-benefit counseling [19]
5. Treatment Implications: Unlike MI, most myocarditis is managed supportively without revascularization; immunosuppression may harm if used inappropriately [5,20]

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Visual Summary

Visual assets to be added:

• ECG comparison: STEMI vs myocarditis (regional vs diffuse ST elevation)
• Cardiac MRI T2 mapping and late gadolinium enhancement patterns
• Myocarditis etiology flowchart (viral, autoimmune, drug-induced, idiopathic)
• Management algorithm by presentation severity
• Histopathology: Dallas criteria vs immunohistochemistry
• Fulminant vs non-fulminant clinical course comparison
• Lake Louise criteria visual summary

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Epidemiology

Incidence and Prevalence

True Incidence Unknown: The reported incidence of 22 per 100,000 person-years significantly underestimates true disease burden due to:

• Subclinical cases never diagnosed (estimated 10-20 fold higher actual incidence) [9]
• Misdiagnosis as "viral syndrome" or "idiopathic chest pain"
• Attribution to other causes in sudden death cases
• Geographic and temporal variation with viral epidemics

Autopsy Studies: Myocarditis found in 1-9% of routine autopsies, rising to 12-20% in young sudden death cases [17,21]

Clinical Cohorts: Among patients with unexplained new-onset heart failure, biopsy-proven myocarditis found in 9-16% [22]

Demographics

Age Distribution:

• Bimodal peak: young adults (20-40 years) and infants/children under 5 years
• Median age at presentation: 33-42 years across large registries [11,23]
• Pediatric myocarditis more commonly fulminant (40-50% vs 15-20% in adults) [24]

Sex Differences:

• Male predominance: 1.5-1.7:1 male-to-female ratio [11]
• Males more likely to present with severe phenotypes
• Possible explanations: hormonal protection in females, testosterone-mediated immune responses, higher male viral susceptibility

Geographic Variation:

• Higher in developed countries (better diagnostic capability)
• Seasonal variation follows viral epidemics (enterovirus peak in late summer/fall)
• Chagas disease endemic regions (Latin America): major cause of myocarditis

Etiological Causes

Infectious Causes (60-70% of cases)

Viral (Most Common): [1,10,25]

Bacterial:

• Corynebacterium diphtheriae: Historical significance; toxin-mediated
• Borrelia burgdorferi: Lyme carditis—presents with AV block
• Streptococcus, Staphylococcus: Direct invasion or toxin-mediated
• Mycoplasma pneumoniae: Rare complication

Parasitic:

• Trypanosoma cruzi: Chagas disease—major cause in Latin America; chronic phase leads to dilated cardiomyopathy
• Toxoplasmosis: In immunocompromised patients

Fungal: Rare; typically immunocompromised (Aspergillus, Candida)

Non-Infectious Causes (30-40%)

Autoimmune and Systemic Inflammatory (15-20%): [29]

• Systemic Lupus Erythematosus: Myocarditis in 8-25% of SLE patients
• Systemic Sclerosis: Cardiac involvement in 15-35%
• Dermatomyositis/Polymyositis: Myocardial inflammation common
• Sarcoidosis: Cardiac involvement in 25-30% (often subclinical); granulomatous inflammation [30]
• Giant Cell Myocarditis: Rapidly progressive; high mortality without immunosuppression [31]
• Eosinophilic Myocarditis: Associated with hypereosinophilic syndrome, Churg-Strauss
• Kawasaki Disease: Pediatric; coronary aneurysms + myocarditis

Drug-Induced (5-10%): [32]

• Immune Checkpoint Inhibitors: Nivolumab, pembrolizumab—severe fulminant myocarditis in 0.1-1% [33]
• Anthracyclines: Doxorubicin, daunorubicin—dose-dependent cardiotoxicity
• Clozapine: 0.7-1.2% incidence; typically in first month of therapy [34]
• Cocaine: Direct toxicity + coronary vasospasm
• Amphetamines: Methamphetamine, MDMA
• Smallpox Vaccine: Historical; 1 in 10,000-30,000 vaccinees
• mRNA COVID-19 Vaccines: Predominantly young males; incidence 1-5 per 100,000, mostly mild [19]

Toxic:

• Alcohol (may overlap with dilated cardiomyopathy)
• Heavy metals (copper, iron, lead)
• Carbon monoxide

Idiopathic (15-20%): No cause identified despite thorough evaluation

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Pathophysiology

Three-Phase Model of Viral Myocarditis

Viral myocarditis follows a triphasic course from initial infection to either recovery or chronic cardiomyopathy: [35]

Phase 1: Viral Entry and Direct Injury (Days 1-7)

Mechanism:

1. Viral Binding: Viruses (especially enteroviruses) bind to the coxsackie-adenovirus receptor (CAR) on cardiomyocyte surface
2. Cellular Entry: Viral internalization and replication within myocytes
3. Direct Cytopathic Effect: Viral replication causes myocyte necrosis and apoptosis
4. Protease Activation: Viral proteases cleave dystrophin and other cytoskeletal proteins, disrupting cellular architecture [36]

Clinical Correlate: Viral prodrome—fever, myalgia, upper respiratory or gastrointestinal symptoms

Phase 2: Immune Activation (Days 7-14)

Innate Immunity:

• Pattern recognition receptors (TLRs) detect viral PAMPs
• Activation of interferon pathways and cytokine release (IL-1β, IL-6, TNF-α)
• Natural killer cell recruitment
• Complement activation

Adaptive Immunity:

• Antigen presentation activates CD4+ and CD8+ T cells
• Cytotoxic T lymphocytes attack infected and uninfected myocytes (molecular mimicry)
• Autoantibody production against cardiac antigens (myosin, troponin, β1-adrenergic receptor) [37]
• B cell activation and antibody-mediated injury

Myocardial Damage:

• Inflammatory infiltrate (lymphocytes, macrophages, eosinophils depending on etiology)
• Myocyte necrosis and apoptosis from immune attack
• Interstitial edema
• Microvascular dysfunction

Clinical Correlate: Cardiac symptoms emerge—chest pain, dyspnea, arrhythmias; troponin elevation; ECG changes

Phase 3: Resolution or Progression (Weeks to Months)

Three possible outcomes:

A. Complete Resolution (60-70%):

• Viral clearance
• Downregulation of immune response
• Myocardial healing with minimal fibrosis
• Return of normal cardiac function

B. Chronic Persistent Myocarditis (10-15%):

• Failure to clear viral genome (persistent low-level viral presence detected by PCR) [26,27]
• Ongoing low-grade inflammation
• Progressive fibrosis
• Gradual transition to dilated cardiomyopathy
• Chronic heart failure symptoms

C. Dilated Cardiomyopathy (10-25%):

• Extensive myocardial damage and fibrosis
• Ventricular remodeling and dilatation
• Persistent systolic dysfunction
• Clinical heart failure requiring long-term management [6,7]

Molecular Mechanisms

Genetic Susceptibility:

• HLA-DQ and HLA-DR alleles associated with increased susceptibility and worse outcomes [38]
• Polymorphisms in cytokine genes (TNF-α, IL-10) influence disease severity
• Dystrophin mutations may predispose to viral entry

Autoimmune Perpetuation:

• Molecular mimicry: viral antigens share epitopes with cardiac proteins [37]
• Epitope spreading: immune response expands to additional cardiac antigens
• Autoantibodies to β1-adrenergic receptor correlate with worse outcomes [39]

Microvascular Dysfunction:

• Endothelial activation and increased permeability
• Microthrombi formation
• Impaired myocardial perfusion despite normal epicardial coronaries

Special Pathophysiology: Fulminant Myocarditis

Defining Features: [8,40]

• Acute onset (less than 3 weeks from symptom to severe presentation)
• Severe hemodynamic compromise requiring inotropes or mechanical support
• Relatively preserved left ventricular dimensions (distinct from acute-on-chronic DCM)
• Extensive myocardial inflammation on biopsy

Paradoxical Prognosis:

• Higher acute mortality (40-50% without mechanical support)
• BUT better long-term outcome if survive acute phase (~93% transplant-free survival at 11 years) [8]
• Complete histological resolution more common than chronic/persistent myocarditis

Proposed Mechanism for Better Long-term Outcome:

• Overwhelming acute immune response effectively clears virus
• Less chronic viral persistence
• Less autoimmune perpetuation
• More complete resolution once acute phase controlled

Histopathology

Dallas Criteria (1987): [41]

• Definite Myocarditis: Inflammatory infiltrate + myocyte necrosis/degeneration not typical of ischemia
• Borderline Myocarditis: Inflammatory infiltrate without clear myocyte damage
• No Myocarditis: No inflammation

Limitations of Dallas Criteria:

• Poor inter-observer reproducibility
• Low sensitivity due to sampling error (patchy distribution)
• Does not specify etiology or guide treatment

Immunohistochemistry and Molecular Techniques:

• CD3+ T cells (lymphocytic myocarditis)
• CD68+ macrophages
• Viral PCR to detect viral genomes (parvovirus B19, HHV-6, enterovirus) [26]

• 14 leucocytes/mm² suggests active myocarditis [4]

Specific Histological Subtypes:

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Clinical Presentation

Classical Presentation Triad

The classic presentation includes:

1. Chest Pain (60-70%)
2. Heart Failure Symptoms (50-70%)
3. Arrhythmias or Palpitations (30-50%)

However, the complete triad is present in only 30-40% of patients. [1,23]

Symptom Profile

Chest Pain

• Character: Pleuritic, positional, sharp (suggests pericardial involvement—myopericarditis)
• OR Pressure-like, substernal (mimics angina)
• Duration: Persistent (unlike crescendo angina)
• Radiation: May radiate to neck, arms
• Exacerbating Factors: Deep inspiration, lying flat (if pericardial component)
• Relieving Factors: Sitting forward (myopericarditis); not relieved by nitrates

Heart Failure Symptoms

• Dyspnea: Exertional progressing to rest; orthopnea; paroxysmal nocturnal dyspnea
• Fatigue: Profound, disproportionate to exertion
• Peripheral Edema: Lower extremities; may progress to anasarca
• Abdominal Distension: Ascites in severe cases
• Rapid Onset: Hours to days in fulminant cases

Arrhythmia-Related Symptoms

• Palpitations: Awareness of irregular or rapid heartbeat
• Presyncope or Syncope: Suggests ventricular arrhythmia or high-grade AV block
• Sudden Cardiac Arrest: May be the presenting event in 5-10%

Systemic Symptoms

• Viral Prodrome (50-80%): Fever, myalgia, upper respiratory symptoms, gastrointestinal symptoms (nausea, vomiting, diarrhea)
• Timeline: Cardiac symptoms typically 1-3 weeks after viral illness

Clinical Phenotypes

1. Subclinical Myocarditis

• Asymptomatic or minimal symptoms
• Discovered incidentally (mild troponin elevation, ECG changes)
• May present years later with "idiopathic" dilated cardiomyopathy

2. Acute Myocarditis (Most Common)

• Gradual symptom onset over days to weeks
• Mild to moderate heart failure
• Preserved hemodynamics
• LVEF 30-50%

3. Fulminant Myocarditis (10-15%)

• Rapid onset (less than 3 weeks symptom to presentation) [8,40]
• Cardiogenic shock requiring inotropes or mechanical support
• Normal or near-normal LV dimensions (vs dilated in chronic DCM)
• Severe hemodynamic compromise
• High acute mortality BUT better long-term prognosis

4. Chronic Active Myocarditis

• Persistent symptoms > 3 months
• Progressive ventricular dysfunction
• Biopsy shows ongoing inflammation
• Risk of progression to DCM

5. Arrhythmic Presentation

• Dominant feature: ventricular tachycardia, ventricular fibrillation, or high-grade AV block
• May have minimal heart failure symptoms
• Sudden cardiac death risk
• Lyme carditis classically presents with AV block

Physical Examination Findings

Vital Signs

• Tachycardia: Disproportionate to fever or activity (sinus tachycardia most common)
• Hypotension: Suggests cardiogenic shock
• Fever: Present in 20-40%; higher in infectious etiologies
• Tachypnea: If pulmonary edema

Cardiovascular Examination

Inspection:

• Visible apical impulse (displaced in DCM)
• Elevated jugular venous pressure (right heart failure)

Palpation:

• Displaced or diffuse apical impulse
• Parasternal heave (RV involvement)

Auscultation:

• S3 Gallop: Most consistent finding suggesting systolic dysfunction and elevated filling pressures
• S4: May be present
• Mitral Regurgitation Murmur: Functional MR from ventricular dilatation
• Pericardial Friction Rub: If concurrent pericarditis (myopericarditis in 20-40%)

Respiratory Examination

• Crackles: Bilateral basal in pulmonary edema
• Dullness to Percussion: Pleural effusions

Peripheral Examination

• Peripheral Edema: Lower limbs; may extend to sacrum if bed-bound
• Cool Extremities: Poor perfusion in shock
• Ascites and Hepatomegaly: Right heart failure

Red Flags — Require Immediate Assessment

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Clinical Examination

Systematic Cardiovascular Examination

Inspection

• General appearance: Distressed, comfortable at rest, or requiring upright positioning
• Respiratory distress: Tachypnea, use of accessory muscles
• Central cyanosis: Severe heart failure
• JVP: Elevated with prominent "v" waves (functional TR)

Palpation

• Radial Pulse: Rate, rhythm, character, volume
  • Tachycardia common
  • Irregular if atrial fibrillation
  • Low volume in cardiogenic shock
• Apex Beat: Position, character
  • Displaced laterally and inferiorly in dilated cardiomyopathy
  • Diffuse, hypokinetic
  • Thrusting apex suggests preserved function
• Parasternal Heave: Right ventricular involvement or pulmonary hypertension

Auscultation

• Heart Sounds:
  • "S1: May be diminished"
  • "S2: Normally split; single S2 if severe LV dysfunction"
  • "S3 Gallop: Key finding—suggests elevated LV end-diastolic pressure"
  • "S4: May be present with diastolic dysfunction"
• Murmurs:
  • "Pansystolic murmur at apex: Functional mitral regurgitation"
  • "Pansystolic at left sternal edge: Functional tricuspid regurgitation"
• Pericardial Rub: High-pitched scratching sound; myopericarditis

Respiratory Examination

• Bilateral fine basal crackles: Pulmonary edema
• Reduced breath sounds and dullness: Pleural effusions

Peripheral Examination

• Pitting edema: Lower limbs, sacrum
• Hepatomegaly: Pulsatile if severe TR
• Ascites: Decompensated right heart failure
• Cool peripheries, prolonged capillary refill: Cardiogenic shock

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Investigations

Blood Tests

Viral and Autoimmune Serology

Limited Clinical Utility: Serological testing rarely changes acute management and is not routinely recommended. [1,4]

• Viral Serology: IgM/IgG for enterovirus, adenovirus, parvovirus B19, EBV, CMV, HIV, SARS-CoV-2
  • IgM suggests recent infection but does not confirm myocardial involvement
  • Often negative in biopsy-proven viral myocarditis
• Autoantibodies: ANA, dsDNA, ANCA, anti-Ro/La if systemic disease suspected
• Lyme Serology: If geographic risk and AV block present
• Chagas Serology: If endemic area exposure

Indication: Reserve for cases where specific etiology would change management (e.g., Lyme disease → antibiotics; autoimmune → immunosuppression consideration)

Electrocardiogram (ECG)

ECG Abnormalities Present in 80-90% of Cases: [12]

Common Findings

Distinguishing Myocarditis from STEMI on ECG

Clinical Implication: If ECG shows diffuse ST elevation + PR depression + absence of reciprocal changes → consider myopericarditis before activating catheterization lab

Echocardiography

Transthoracic Echocardiography (TTE): First-line imaging — widely available, non-invasive, provides immediate hemodynamic assessment [1]

Key Findings

Left Ventricular Function:

• Global Hypokinesis: Most common pattern (50-60%)
• Regional Wall Motion Abnormalities: May mimic coronary distribution (20-30%)
• LVEF: Variable—normal to severely reduced (less than 20%)
• LV Dimensions: Normal or mildly increased in acute myocarditis; dilated in chronic or fulminant cases

Right Ventricular Involvement:

• RV dysfunction in 30-40%
• Prognostic significance—worse outcomes [44]

Pericardial Effusion:

• Small to moderate effusion in 30-50% (myopericarditis)
• Tamponade rare

Valvular Abnormalities:

• Functional mitral or tricuspid regurgitation due to ventricular dilatation

Other Features:

• Increased wall thickness (myocardial edema)
• Diastolic dysfunction
• LV thrombus (rare; anticoagulate if present)

Limitations:

• Non-specific findings
• Cannot confirm diagnosis
• Normal echo does not exclude myocarditis

Cardiac Magnetic Resonance Imaging (CMR)

Gold Standard Non-Invasive Diagnostic Test: [2,3]

Lake Louise Criteria (Updated 2018)

Diagnosis Requires:

• At least 1 T2-based criterion (myocardial edema) AND
• At least 1 T1-based criterion (myocardial injury/fibrosis)

T2-Based Criteria (Edema — Active Inflammation):

1. Global or regional T2 increase (myocardial edema ratio > 2.0 or regional T2 relaxation time elevation)
2. High T2 signal intensity on T2-weighted images

T1-Based Criteria (Injury/Fibrosis):

1. Increased global myocardial T1 (native T1 mapping)
2. Increased extracellular volume (ECV)
3. Late Gadolinium Enhancement (LGE): Non-ischemic pattern

LGE Patterns in Myocarditis: [45]

• Subepicardial or midwall (NOT subendocardial like infarction)
• Patchy distribution
• Inferolateral wall most commonly affected
• Absence of LGE does not exclude myocarditis (present in only 60-70%)

Additional CMR Parameters:

• Early Gadolinium Enhancement (EGE): Hyperemia/capillary leak
• Pericardial Enhancement: Myopericarditis
• Global Longitudinal Strain: Sensitive marker of dysfunction

Prognostic Value:

• Presence of LGE associated with increased mortality and arrhythmia risk [46]
• Midwall LGE pattern worse prognosis than subepicardial
• Extent of LGE correlates with outcomes

Sensitivity and Specificity:

• Sensitivity: 75-85% (updated criteria) [3]
• Specificity: 80-90%
• Highest accuracy within first 2 weeks of symptom onset

Limitations:

• Expensive, limited availability
• Contraindications: severe renal impairment (gadolinium), pacemakers/ICDs (relative), claustrophobia
• Technical expertise required
• False negatives possible (normal CMR in 10-20% of biopsy-proven myocarditis)

Endomyocardial Biopsy (EMB)

Histological Gold Standard: [4]

Indications for EMB (AHA/ACC/ESC Scientific Statement): [4,47]

Class I (Recommended):

• Unexplained new-onset heart failure less than 2 weeks with hemodynamic compromise despite optimal therapy
• Unexplained heart failure 2 weeks to 3 months with:
  • Ventricular arrhythmias
  • High-grade AV block
  • Failure to respond to standard therapy

Class IIa (Reasonable):

• Suspected giant cell myocarditis, eosinophilic myocarditis, or cardiac sarcoidosis (change in management with immunosuppression)
• Suspected anthracycline cardiomyopathy

Not Routinely Recommended:

• Stable chronic heart failure
• Mild acute myocarditis with preserved hemodynamics
• Cases where diagnosis established by CMR and management will not change

Technique:

• Right ventricular septum via internal jugular or femoral vein
• Minimum 3-5 samples (ideally 5-7) due to patchy distribution
• Samples for:
  • Histology (Dallas criteria, immunohistochemistry)
  • Viral PCR (enterovirus, parvovirus B19, HHV-6, adenovirus) [26]
  • Special stains (granulomas, eosinophils, giant cells)

Histological Findings:

• Lymphocytic Infiltrate: > 14 leucocytes/mm² [4]
• Myocyte Necrosis: Not typical of ischemic pattern
• CD3+ T Cells: T-lymphocyte predominance
• Viral Genome: PCR positivity in 25-40% (European data higher for parvovirus B19) [26]

Complications:

• Cardiac perforation (0.5-1%)
• Tamponade (0.5%)
• Arrhythmias (transient)
• Tricuspid regurgitation
• Mortality less than 0.1%

Limitations:

• Sampling Error: Patchy distribution leads to false negatives (sensitivity 20-50%) [4]
• Invasive procedure with risks
• Expertise required for interpretation (poor inter-observer agreement with Dallas criteria)

Coronary Angiography

Indications:

• STEMI cannot be excluded clinically → proceed to catheterization lab as per ACS protocol
• Troponin elevation + chest pain in patient with cardiac risk factors
• Age > 40 years with typical anginal symptoms

Findings:

• Normal Coronaries: Expected in myocarditis
• Slow Flow Phenomenon: Microvascular dysfunction
• Spontaneous Coronary Artery Dissection (SCAD): Differential diagnosis in young women

Left Ventriculography:

• May show global or regional hypokinesis
• NOT routinely performed (risk of mechanical complications in inflamed myocardium)

Other Investigations

Chest X-Ray:

• Cardiomegaly (cardiothoracic ratio > 0.5) suggests ventricular dilatation
• Pulmonary edema (interstitial or alveolar)
• Pleural effusions

Holter Monitor (24-48 Hour):

• Detect paroxysmal arrhythmias (non-sustained VT, atrial fibrillation)
• Risk stratification for sudden death

Cardiopulmonary Exercise Testing:

• Assess functional capacity
• Guide return to activity decisions
• Peak VO2 less than 14 mL/kg/min suggests poor prognosis

Genetic Testing:

• Consider if family history of cardiomyopathy or sudden death
• May reveal underlying inherited cardiomyopathy precipitated by myocarditis

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Differential Diagnosis

Myocarditis mimics many cardiac and non-cardiac conditions:

Cardiac Differentials

Non-Cardiac Differentials

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Management

General Principles

Management of myocarditis is predominantly supportive, focusing on:

1. Hemodynamic stabilization
2. Heart failure treatment
3. Arrhythmia management
4. Activity restriction
5. Monitoring for complications
6. Treatment of specific etiologies (when identified)

NO PROVEN DISEASE-MODIFYING THERAPY exists for typical viral/lymphocytic myocarditis. [1,5]

Acute Management — Hemodynamically Stable

1. Admission and Monitoring

• Telemetry Monitoring: Continuous ECG monitoring for arrhythmia detection
• Serial Troponin: Monitor myocardial injury trend
• Daily Clinical Assessment: Symptoms, volume status, cardiac examination
• Repeat Echocardiography: If clinical deterioration or new murmur

2. Heart Failure Therapy

ACE Inhibitors or ARBs: [48]

• Reduce afterload and ventricular remodeling
• Start low dose (risk of hypotension in acute phase)
• Titrate to target doses as tolerated
• Examples: Ramipril 2.5-10 mg daily; Enalapril 2.5-20 mg BD

Beta-Blockers: [48]

• Delay initiation until hemodynamically stable (risk of cardiogenic shock if started too early)
• Reduce sympathetic drive, improve outcomes in heart failure
• Start at low dose and titrate slowly
• Examples: Bisoprolol 1.25-10 mg daily; Carvedilol 3.125-25 mg BD

Diuretics:

• Furosemide for volume overload (pulmonary edema, peripheral edema)
• Titrate to euvolemia; avoid over-diuresis (hypotension)
• Monitor renal function and electrolytes

Mineralocorticoid Receptor Antagonists:

• Spironolactone 25-50 mg daily if LVEF less than 40%
• Monitor potassium and renal function

SGLT2 Inhibitors:

• Emerging evidence for benefit in heart failure with reduced ejection fraction
• Dapagliflozin 10 mg or empagliflozin 10 mg daily
• Consider once stabilized

Anticoagulation:

• Consider if:
  • LVEF less than 30%
  • LV thrombus identified
  • Atrial fibrillation
• Warfarin (target INR 2-3) or DOAC

3. Arrhythmia Management

Ventricular Arrhythmias:

• Amiodarone for sustained VT or recurrent non-sustained VT
• Cardioversion for hemodynamically unstable VT/VF
• Avoid class IC agents (flecainide, propafenone) — may worsen inflammation

Atrial Fibrillation:

• Rate control (beta-blocker, digoxin)
• Anticoagulation as per CHA₂DS₂-VASc score
• Consider cardioversion if new-onset and hemodynamically compromised

AV Block:

• Temporary Pacing for symptomatic bradycardia or high-grade AV block
• Lyme Carditis: Treat with antibiotics (ceftriaxone); AV block often resolves [43]
• Permanent pacemaker NOT indicated acutely (conduction disease often resolves)

4. Activity Restriction

CRITICAL: Restrict physical activity to reduce sudden cardiac death risk. [16]

• Avoid All Strenuous Exercise for 3-6 months minimum
• No competitive sports
• Light activities of daily living permitted
• Rationale: Exercise-induced catecholamine surge + inflammation increases arrhythmia and sudden death risk

Return to Activity Criteria:

• Symptom resolution
• Normalization of LV function (LVEF > 50-55%)
• No arrhythmias on Holter monitoring
• Normal or near-normal CMR (resolution of edema)
• Negative exercise stress test

5. Medications to AVOID

Fulminant Myocarditis — Intensive Care

Definition: Severe hemodynamic compromise requiring inotropes or mechanical circulatory support. [8,40]

1. ICU Admission

• Invasive monitoring: arterial line, central venous access
• Continuous telemetry
• Multidisciplinary team: cardiology, intensive care, cardiac surgery

2. Hemodynamic Support

Inotropic Agents:

• Dobutamine: 2.5-20 μg/kg/min (beta-agonist; increases contractility and reduces afterload)
• Milrinone: 0.375-0.75 μg/kg/min (phosphodiesterase inhibitor; inotrope and vasodilator)
• Noradrenaline: Add if vasoplegic shock (low SVR despite inotropes)

Mechanical Circulatory Support (MCS): [49]

VA-ECMO Considerations:

• Provides complete cardiopulmonary support
• Allows myocardial rest and recovery
• Complications: bleeding, thromboembolism, limb ischemia, infection
• Bridge to recovery (60-70% wean successfully) OR bridge to transplant/LVAD [49]

3. Endomyocardial Biopsy

• Strongly consider in fulminant cases to identify treatable etiologies (giant cell, eosinophilic, sarcoidosis) [4,47]

4. Heart Transplantation

• Consider if refractory despite maximal support
• Fulminant myocarditis indication for urgent transplant listing
• Excellent post-transplant outcomes

Immunosuppressive Therapy

NOT Routinely Recommended for typical lymphocytic myocarditis. [5,20]

Evidence:

• Myocarditis Treatment Trial (1995): No benefit of immunosuppression (prednisone + azathioprine vs placebo) in biopsy-proven myocarditis [20]
• May worsen viral replication in acute viral myocarditis

Specific Indications for Immunosuppression:

Giant Cell Myocarditis Protocol: [31]

• Cyclosporine (target level 150-250 ng/mL) + prednisone 1 mg/kg
• Add azathioprine or mycophenolate
• Dramatically improved survival vs historical controls (transplant-free survival ~50% at 5 years vs less than 20%)

Etiology-Specific Treatment

Lyme Carditis (Borrelia burgdorferi): [43]

• Antibiotics: Ceftriaxone 2 g IV daily × 14-21 days OR doxycycline 100 mg BD PO × 21 days (if mild)
• Temporary pacing if high-grade AV block
• AV block typically resolves with antibiotic therapy

Chagas Disease (Trypanosoma cruzi):

• Acute Phase: Benznidazole or nifurtimox (antiparasitic)
• Chronic Phase: Supportive heart failure management; antiparasitic therapy less effective

Drug-Induced Myocarditis:

• STOP Offending Drug (checkpoint inhibitors, clozapine, etc.)
• Checkpoint inhibitor myocarditis: High-dose steroids ± additional immunosuppression [33]

Autoimmune Myocarditis:

• Treat underlying systemic disease (SLE, sarcoidosis, etc.)
• Steroids and disease-modifying agents as per rheumatology/systemic disease protocols

Follow-Up and Long-Term Management

Outpatient Follow-Up:

• Cardiology review at 2-4 weeks, then 3 months, then 6 months
• Serial echocardiography to monitor LV function recovery
• Consider repeat CMR at 3-6 months to assess resolution of inflammation and LGE

Repeat CMR Indications:

• Persistent symptoms
• Lack of LV function recovery
• Before return to competitive sports

Holter Monitoring:

• Assess for arrhythmias before return to activity
• If high-burden VT/VF or residual LV dysfunction → consider ICD

ICD Indications: [50]

• Severely reduced LVEF less than 35% persisting > 3 months despite optimal medical therapy
• Sustained VT/VF beyond acute phase
• Aborted sudden cardiac death

Permanent Pacemaker:

• Rarely needed (most AV block resolves)
• Consider if persistent high-grade AV block beyond 2-3 weeks

Lifestyle Counseling:

• Activity restriction 3-6 months
• Avoid alcohol
• Family screening NOT routinely indicated (unless genetic cardiomyopathy suspected)

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Complications

Acute Complications

Chronic Complications

Dilated Cardiomyopathy: [6,7]

• Incidence: 10-25% progress to DCM
• Risk Factors: Severe LV dysfunction at presentation, extensive LGE on CMR, failure to recover EF, persistent viral genome
• Management: Long-term heart failure therapy; transplant evaluation if refractory

Chronic Heart Failure:

• Reduced exercise tolerance
• Recurrent hospitalizations
• Requires lifelong medical therapy

Recurrent Myocarditis:

• 10-15% experience recurrence
• May suggest autoimmune etiology

Arrhythmias:

• Atrial fibrillation
• Ventricular arrhythmias from myocardial scar (LGE regions)

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Prognosis and Outcomes

Overall Prognosis

Variable Outcomes: [6,7,8]

• 60-70%: Complete recovery with normalization of LV function
• 10-25%: Progression to dilated cardiomyopathy
• 5-10%: Death or transplantation

Mortality

In-Hospital Mortality: 1-7% overall [14]

• Lower in mild cases (less than 1%)
• Higher in fulminant myocarditis (40-50% without mechanical support; 10-20% with MCS) [8]

Long-Term Mortality: Primarily driven by progression to DCM and heart failure

Factors Predicting Poor Prognosis

Clinical:

• Syncope at presentation
• NYHA class III-IV symptoms
• Need for inotropic support

Hemodynamic:

• LVEF less than 30-35%
• Right ventricular dysfunction [44]
• Elevated LV end-diastolic pressure

Biomarkers:

• Markedly elevated troponin (> 50-100× upper limit normal)
• Severely elevated BNP/NT-proBNP

ECG:

• QRS duration > 120 ms
• Pathological Q waves
• Sustained ventricular arrhythmias

Imaging:

• Extensive LGE on CMR (> 20% of LV mass) [46]
• Midwall LGE pattern worse than subepicardial
• Persistent LV dysfunction at 3-6 months

Histology:

• Giant cell myocarditis (rapidly progressive; high mortality without immunosuppression) [31]
• Extensive myocyte necrosis

Factors Predicting Good Prognosis

• Young age
• Acute presentation without prior cardiac history
• Fulminant presentation (paradoxically better long-term prognosis if survive acute phase) [8]
• Preserved or mildly reduced LVEF
• No extensive LGE on CMR
• Complete resolution of symptoms and LV function by 6 months

Fulminant vs Non-Fulminant Long-Term Outcomes

Paradoxical Prognostic Relationship: [8,40]

Return to Exercise and Sports

Timeline: [16]

• Minimum 3-6 months abstinence from competitive sports
• Gradual return under supervision

Criteria for Return:

1. Complete symptom resolution
2. Normalization of LV function (LVEF > 50-55%)
3. Normal or near-normal CMR (resolution of edema; stable LGE)
4. No arrhythmias on 24-48 hour Holter
5. Negative exercise stress test
6. Normal biomarkers (troponin, BNP)

Shared Decision-Making: Some athletes with residual LGE may accept higher risk; individualized approach

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Evidence and Guidelines

Key Guidelines

1. European Society of Cardiology (ESC) Position Statement on Myocarditis (2013): [1]

   • Comprehensive review of diagnosis and management
   • Lake Louise criteria for CMR
   • EMB indications
   • PMID: 23824828

2. AHA/ACC/ESC Scientific Statement on Endomyocardial Biopsy (2007): [4]

   • Class I and IIa indications for EMB
   • Histological and immunohistochemical criteria
   • PMID: 17938300

3. Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation (2018): [3]

   • Updated Lake Louise criteria
   • T1 and T2 mapping techniques
   • PMID: 30545455

4. AHA Scientific Statement on Myocarditis (2009): [47]

   • Clinical presentation and diagnosis
   • Management strategies
   • PMID: 19228821

Key Evidence

Diagnostic Studies:

• Ferreira VM et al. (2018): Updated Lake Louise criteria improve diagnostic accuracy of CMR [3]
• Friedrich MG et al. (2009): Original Lake Louise criteria validation [2]

Prognostic Studies:

• Grun S et al. (2012): Long-term follow-up of biopsy-proven myocarditis; LGE predicts outcomes [46]
• Ammirati E et al. (2018): Contemporary cohort demonstrating clinical presentation and outcomes [23]

Treatment Studies:

• Mason JW et al. (1995): Myocarditis Treatment Trial—no benefit of immunosuppression in lymphocytic myocarditis [20]
• Ginsberg F et al. (2012): Multicenter registry of giant cell myocarditis; improved outcomes with immunosuppression [31]
• Cooper LT et al. (2008): Fulminant vs non-fulminant myocarditis outcomes [8]

Mechanistic Studies:

• Kuethe F et al. (2007): Parvovirus B19 and HHV-6 persistence in myocarditis [26]
• Caforio AL et al. (2008): Autoantibodies in myocarditis and dilated cardiomyopathy [39]

COVID-19 and Vaccine-Associated Myocarditis:

• Boehmer TK et al. (2021): Myocarditis following mRNA COVID-19 vaccination [19]
• Ammirati E et al. (2021): COVID-19-associated myocarditis [28]

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Patient and Family Information

What is Myocarditis?

Myocarditis is inflammation of the heart muscle (myocardium). It is most often caused by a viral infection, but can also result from autoimmune diseases, certain medications, or toxins. The inflammation can affect the heart's ability to pump blood and may cause abnormal heart rhythms.

What Causes It?

• Viral Infection (most common): Often follows a cold, flu, or stomach bug
• Autoimmune Diseases: Lupus, sarcoidosis, and other conditions where the immune system attacks the body
• Medications: Some drugs (chemotherapy, certain antibiotics, recreational drugs)
• Unknown: In many cases, the exact cause is never found

What Are the Symptoms?

• Chest pain (may feel sharp or like pressure)
• Shortness of breath
• Extreme tiredness
• Palpitations (feeling your heart racing or fluttering)
• Swelling in your legs or abdomen
• Feeling faint or fainting

When to Seek Emergency Help:

• Severe chest pain
• Difficulty breathing at rest
• Fainting
• Rapid or irregular heartbeat that won't stop

How is it Diagnosed?

• Blood Tests: Troponin (heart muscle injury marker), BNP (heart function marker)
• ECG: Checks heart rhythm and electrical activity
• Echocardiogram: Ultrasound of the heart to assess pumping function
• Cardiac MRI: Detailed scan showing inflammation and scarring
• Heart Biopsy: Rarely needed; small samples taken from heart muscle

How is it Treated?

Most Cases:

• Rest: Avoid strenuous activity for 3-6 months
• Medications: Heart failure medications (ACE inhibitors, beta-blockers, diuretics)
• Monitoring: Regular check-ups to ensure recovery

Severe Cases:

• Intensive care unit (ICU) monitoring
• Medications to support heart pumping (inotropes)
• Mechanical heart pumps (ECMO, Impella) as a temporary bridge
• Rarely, heart transplantation

Medications to Avoid:

• Anti-inflammatory drugs (ibuprofen, naproxen)—use paracetamol for pain instead
• Alcohol

What is the Outlook?

• Most People Recover Fully (60-70%): Heart function returns to normal within weeks to months
• Some Develop Long-Term Heart Problems (10-25%): May need lifelong medications
• Severe Cases: Can be life-threatening, but with advanced support, many still recover

When Can I Return to Normal Activities?

• Light Activity: As tolerated once symptoms improve
• Strenuous Exercise and Sports: Not for 3-6 months minimum
• Your doctor will perform tests (echocardiogram, heart MRI, heart rhythm monitoring) before clearing you to resume full activity
• Athletes: Must be cleared by a cardiologist before returning to competitive sports

Follow-Up

• Regular cardiology appointments (2 weeks, 3 months, 6 months)
• Repeat heart scans to monitor recovery
• Heart rhythm monitoring (Holter monitor)

Resources and Support

• British Heart Foundation: www.bhf.org.uk
• Cardiomyopathy UK: www.cardiomyopathy.org
• Myocarditis Foundation: www.myocarditisfoundation.org
• American Heart Association: www.heart.org

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References

Guidelines and Position Statements

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2. Friedrich MG, Sechtem U, Schulz-Menger J, et al. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol. 2009;53(17):1475-1487. doi:10.1016/j.jacc.2009.02.007. PMID: 19389557

3. Ferreira VM, Schulz-Menger J, Holmvang G, et al. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations. J Am Coll Cardiol. 2018;72(24):3158-3176. doi:10.1016/j.jacc.2018.09.072. PMID: 30545455

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Epidemiology and Natural History

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Etiology and Pathophysiology

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Diagnosis

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24. Sachdeva S, Song X, Dham N, Heath DM, DeBiasi RL. Analysis of clinical parameters and cardiac magnetic resonance imaging as predictors of outcome in pediatric myocarditis. Am J Cardiol. 2015;115(4):499-504. doi:10.1016/j.amjcard.2014.11.029. PMID: 25542394

25. Bowles NE, Ni J, Kearney DL, et al. Detection of viruses in myocardial tissues by polymerase chain reaction. evidence of adenovirus as a common cause of myocarditis in children and adults. J Am Coll Cardiol. 2003;42(3):466-472. doi:10.1016/s0735-1097(03)00648-x. PMID: 12906974

26. Kühl U, Pauschinger M, Noutsias M, 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. PMID: 15699250

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28. Ammirati E, Lupi L, Palazzini M, et al. Prevalence, characteristics, and outcomes of COVID-19-associated acute myocarditis. Circulation. 2022;145(15):1123-1139. doi:10.1161/CIRCULATIONAHA.121.056817. PMID: 35078342

29. Caforio AL, Marcolongo R, Jahns R, Fu M, Felix SB, Iliceto S. Immune-mediated and autoimmune myocarditis: clinical presentation, diagnosis and management. Heart Fail Rev. 2013;18(6):715-732. doi:10.1007/s10741-012-9364-5. PMID: 23070542

30. Birnie DH, Sauer WH, Bogun F, et al. HRS expert consensus statement on the diagnosis and management of arrhythmias associated with cardiac sarcoidosis. Heart Rhythm. 2014;11(7):1305-1323. doi:10.1016/j.hrthm.2014.03.043. PMID: 24819193

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33. Mahmood SS, Fradley MG, Cohen JV, et al. Myocarditis in patients treated with immune checkpoint inhibitors. J Am Coll Cardiol. 2018;71(16):1755-1764. doi:10.1016/j.jacc.2018.02.037. PMID: 29567210

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44. Hsiao JF, Koshino Y, Bonnichsen CR, et al. Speckle tracking echocardiography in acute myocarditis. Int J Cardiovasc Imaging. 2013;29(2):275-284. doi:10.1007/s10554-012-0085-6. PMID: 22527300

45. Francone M, Chimenti C, Galea N, et al. CMR sensitivity varies with clinical presentation and extent of cell necrosis in biopsy-proven acute myocarditis. JACC Cardiovasc Imaging. 2014;7(3):254-263. doi:10.1016/j.jcmg.2013.10.011. PMID: 24560214

46. Grün S, Schumm J, Greulich S, et al. Long-term follow-up of biopsy-proven viral myocarditis: predictors of mortality and incomplete recovery. J Am Coll Cardiol. 2012;59(18):1604-1615. doi:10.1016/j.jacc.2012.01.007. PMID: 22365425

47. Cooper LT Jr, Baughman KL, Feldman AM, et al. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology. J Am Coll Cardiol. 2007;50(19):1914-1931. doi:10.1016/j.jacc.2007.09.008. PMID: 17980265

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49. Diddle JW, Almodovar MC, Rajagopal SK, Rycus PT, Thiagarajan RR. Extracorporeal membrane oxygenation for the support of adults with acute myocarditis. Crit Care Med. 2015;43(5):1016-1025. doi:10.1097/CCM.0000000000000920. PMID: 25654174

50. Zeppenfeld K, Tfelt-Hansen J, de Riva M, et al. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43(40):3997-4126. doi:10.1093/eurheartj/ehac262. PMID: 36017572

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