Myocarditis

Quick Answer: Myocarditis is inflammation of the myocardium presenting with acute heart failure, chest pain, or arrhythmias. Fulminant myocarditis (below 2 weeks onset, severe LV dysfunction EF below 35%, shock) paradoxically has better long-term prognosis than acute myocarditis but requires aggressive ICU support including mechanical circulatory support (IABP, Impella, VA-ECMO). Diagnosis relies on troponin elevation, ECG changes, CMR Lake Louise criteria (T2 edema, LGE, EGE), and endomyocardial biopsy (Dallas criteria). Most cases are viral (Coxsackie B, parvovirus B19, HHV-6, COVID-19) or immune-mediated (checkpoint inhibitors). Management is supportive (ACE-I, beta-blockers, diuretics) with arrhythmia control; immunosuppression reserved for giant cell, eosinophilic, or cardiac sarcoidosis subtypes. [1-5]

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CICM Exam Focus

Written Examination (SAQ)

High-yield topics for CICM Second Part Written:

1. Fulminant vs Acute Myocarditis

   • Clinical definitions and timeframes
   • Haemodynamic profiles and prognostic differences
   • Indications for mechanical circulatory support

2. Diagnostic Approach

   • Troponin interpretation (magnitude and kinetics)
   • ECG patterns (ST elevation mimicking STEMI, diffuse changes, AV blocks)
   • CMR Lake Louise criteria (T2-weighted, T1-weighted, LGE patterns)
   • Endomyocardial biopsy: Dallas criteria, indications, complications

3. Aetiological Classification

   • Viral (Coxsackie B, parvovirus B19, HHV-6, adenovirus, COVID-19)
   • Immune-mediated (checkpoint inhibitors PD-1/PD-L1, autoimmune)
   • Toxic (anthracyclines, clozapine, cocaine)
   • Giant cell, eosinophilic, cardiac sarcoidosis

4. Critical Care Management

   • Supportive therapy (haemodynamics, arrhythmias)
   • Mechanical circulatory support selection (IABP vs Impella vs VA-ECMO)
   • Immunosuppression: when to use and which agents
   • Temporary pacing for high-grade AV block

5. Complications and Prognosis

   • Arrhythmias (VT/VF, AV blocks, atrial fibrillation)
   • Cardiogenic shock pathophysiology
   • Long-term outcomes (recovery vs progression to DCM)
   • Transplant considerations

Viva Voce

Scenario-based questions:

• 32-year-old with chest pain, troponin 85 ng/mL, ECG ST elevation V1-V4 → is this STEMI or myocarditis?
• Fulminant myocarditis in cardiogenic shock → MCS decision-making
• Post-checkpoint inhibitor myocarditis → recognition and management
• Giant cell myocarditis → when to suspect and immunosuppression protocols

Key discussion points:

• Differentiation from acute coronary syndrome
• Lake Louise CMR criteria interpretation
• Mechanical support strategies and timing
• Role of endomyocardial biopsy in 2026
• COVID-19 myocarditis vs vaccine-related myocarditis

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Key Points

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Epidemiology

Incidence and Prevalence

Incidence:

• Clinically apparent myocarditis: 10-22 per 100,000 person-years in general population [25]
• Autopsy studies: myocarditis found in 1-9% of routine autopsies, suggesting significant underdiagnosis [26]
• Sudden cardiac death in young athletes: myocarditis accounts for 5-22% of cases [27]
• ICU admissions: myocarditis represents 0.5-1.5% of all ICU cardiovascular admissions [28]

Age and Gender Distribution:

• Bimodal age distribution: peak in children below 2 years and young adults 20-40 years [29]
• Male predominance: 1.5-2.5:1 male-to-female ratio [30]
• Fulminant myocarditis: more common in women (60% female) and younger patients (mean age 35-42 years) [6]

Mortality and Prognosis

Acute Phase Mortality:

• Overall in-hospital mortality: 3-6% for all-comers with myocarditis [31]
• Fulminant myocarditis requiring ICU admission: 11-40% in-hospital mortality (varies by era and MCS use) [6,15]
• Cardiogenic shock without mechanical support: 50-70% mortality [32]
• VA-ECMO supported fulminant myocarditis: 25-40% in-hospital mortality in contemporary series [15,16]

Long-term Outcomes:

• Fulminant myocarditis survivors: 93% survival at 11 years with complete or near-complete recovery of LV function [6]
• Acute (non-fulminant) myocarditis: 45% develop persistent LV dysfunction, 12% progress to dilated cardiomyopathy (DCM) [33]
• Giant cell myocarditis: 89% mortality at 5.5 years without transplant; median survival 3-6 months untreated [13]
• Checkpoint inhibitor myocarditis: 25-50% mortality, even with aggressive immunosuppression [11,12]

Prognostic Factors:

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Pathophysiology

Cellular Mechanisms

Three-Phase Model of Viral Myocarditis:

Phase I: Viral Entry and Acute Injury (Days 0-7)

• Viral entry via coxsackievirus-adenovirus receptor (CAR) on cardiomyocytes [34]
• Direct viral cytotoxicity: viral protease 2A cleaves dystrophin, disrupting cytoskeleton [35]
• Innate immune activation: pattern recognition receptors (TLRs) detect viral RNA/DNA [36]
• Release of pro-inflammatory cytokines: IL-1β, IL-6, TNF-α, IFN-γ [37]
• Cardiomyocyte necrosis and apoptosis [38]

Phase II: Adaptive Immune Response (Days 7-14)

• T-cell mediated immunity: CD8+ cytotoxic T cells infiltrate myocardium [39]
• CD4+ T helper cells differentiate into Th1 (pro-inflammatory) and Th17 subsets [40]
• Autoimmune activation: molecular mimicry between viral proteins and cardiac antigens (cardiac myosin) [41]
• Production of anti-cardiac antibodies: anti-cardiac myosin, anti-troponin I, anti-β1-adrenergic receptor antibodies [42]
• Persistence of inflammation despite viral clearance [43]

Phase III: Remodelling (Weeks 2-12)

• Two divergent pathways:
  • "Resolution: regulatory T cells (Tregs) dampen inflammation, fibroblast quiescence, myocardial healing [44]"
  • "Progression: chronic inflammation → myocardial fibrosis → dilated cardiomyopathy [45]"
• Matrix metalloproteinases (MMPs) cause extracellular matrix degradation and ventricular dilatation [46]
• Fibrosis mediated by TGF-β and myofibroblast activation [47]

Haemodynamic Consequences

Systolic Dysfunction:

• Reduced contractility due to cardiomyocyte loss and stunning [48]
• LV ejection fraction typically 20-40% in fulminant myocarditis [6]
• Global or regional wall motion abnormalities (may mimic ischaemic patterns) [49]

Diastolic Dysfunction:

• Myocardial oedema increases wall thickness and reduces compliance [50]
• Elevated LV end-diastolic pressure (LVEDP greater than 18 mmHg) [51]
• Restrictive physiology in severe cases [52]

Cardiogenic Shock:

• Occurs in 15-30% of fulminant myocarditis [6]
• Pathophysiology: ↓ cardiac output + ↑ systemic vascular resistance (SVR) + ↑ LV filling pressures [53]
• "Cold and wet" haemodynamic profile: cardiac index below 2.2 L/min/m², PCWP greater than 18 mmHg [54]
• Spiral of deterioration: ↓ coronary perfusion → ↑ myocardial ischaemia → further ↓ contractility [55]

Arrhythmogenesis:

• Inflammation creates heterogeneous conduction: re-entry circuits for VT/VF [56]
• Myocardial oedema stretches AV node and His-Purkinje system: AV blocks [57]
• Cytokine-mediated calcium dysregulation: triggered activity and early afterdepolarisations [58]
• Fibrosis creates substrate for atrial and ventricular arrhythmias [59]

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Aetiology and Classification

Viral Myocarditis (50-70% of cases)

Common Viral Pathogens:

Viral Detection Methods:

• PCR of endomyocardial biopsy: sensitivity 70-85%, specificity 90-95% [67]
• Serology (IgM antibodies): lower specificity, cannot distinguish active infection [68]
• Viral load greater than 500 copies/µg DNA suggests active viral replication [69]

Immune-Mediated Myocarditis

Checkpoint Inhibitor Myocarditis (PD-1/PD-L1/CTLA-4 Inhibitors):

• Incidence: 0.5-1.5% of patients on checkpoint inhibitors [11]
• Drugs: nivolumab, pembrolizumab, atezolizumab, ipilimumab, combination therapy (higher risk) [12]
• Median onset: 30-45 days after therapy initiation (range 1 day to 18 months) [70]
• Mortality: 25-50% despite immunosuppression [11,12]
• Presentation: often with conduction abnormalities (AV block, new LBBB), elevated troponin, myositis overlap [71]
• Diagnosis: clinical suspicion + troponin + ECG/imaging ± biopsy (lymphocytic infiltration) [72]
• Management: immediate cessation of checkpoint inhibitor + high-dose corticosteroids (methylprednisolone 500-1000 mg/day) + consider infliximab or IVIG for refractory cases [73]

Autoimmune Myocarditis:

• Systemic lupus erythematosus (SLE): 5-10% develop clinical myocarditis; lupus myocarditis associated with anti-SSA/Ro antibodies [74]
• Dermatomyositis/polymyositis: cardiac involvement in 15-30%; associated with anti-Jo-1 antibodies [75]
• Rheumatoid arthritis: rare but described; usually subclinical [76]
• Systemic sclerosis: myocardial fibrosis > acute myocarditis [77]

Toxic Myocarditis

Anthracyclines (Doxorubicin, Daunorubicin, Epirubicin):

• Dose-dependent cardiotoxicity: risk increases with cumulative dose greater than 450-550 mg/m² [78]
• Mechanism: free radical formation (oxidative stress) + topoisomerase IIβ inhibition in cardiomyocytes [79]
• Presentation: acute (rare, within days-weeks), early-chronic (1 year), or late-onset (greater than 1 year, up to decades) [80]
• Prevention: dexrazoxane (iron chelator), liposomal formulations [81]

Clozapine:

• Incidence of myocarditis: 0.5-3%, usually within first 4 weeks of treatment [82]
• Mechanism: IgE-mediated hypersensitivity reaction (Type I) + direct toxic effect [83]
• Presentation: fever, chest pain, tachycardia, eosinophilia (70%), elevated troponin [84]
• Mortality: 10-20% if unrecognised; requires immediate cessation [85]
• Diagnosis: troponin + eosinophilia + CMR or biopsy [86]

Cocaine:

• Mechanism: catecholamine surge + coronary vasospasm + direct toxic metabolites [87]
• Difficult to distinguish from ACS; both may coexist [88]

Other Toxins:

• Heavy metals (copper, iron, lead)
• Carbon monoxide
• Snake/insect venoms
• Amphetamines

Giant Cell Myocarditis

Epidemiology and Prognosis:

• Rare: below 1% of myocarditis cases [89]
• Median age: 42 years; no gender predominance [13]
• Rapidly progressive: median survival 3-6 months untreated, 89% mortality at 5.5 years without transplant [13]

Pathology:

• Multinucleated giant cells + diffuse lymphocytic infiltration + extensive myocyte necrosis [90]
• No granulomas (distinguishes from cardiac sarcoidosis) [91]

Clinical Features:

• Rapidly progressive heart failure (weeks) [92]
• Ventricular arrhythmias (VT/VF) in 65% [93]
• AV block in 25% [94]

Associations:

• Autoimmune diseases: thymoma (16%), inflammatory bowel disease (8%), autoimmune thyroiditis [95]
• Drug-induced hypersensitivity reactions [96]

Management:

• Urgent immunosuppression: corticosteroids (prednisone 1 mg/kg/day or methylprednisolone pulse) + calcineurin inhibitor (cyclosporine 3-5 mg/kg/day or tacrolimus) + azathioprine (2 mg/kg/day) or mycophenolate [97,98]
• Early transplant referral: only definitive treatment with 5-year survival 71% post-transplant [99]
• Mechanical circulatory support as bridge to transplant [100]

Eosinophilic Myocarditis

Causes:

• Hypersensitivity reactions: antibiotics (sulfonamides, penicillins), NSAIDs, diuretics, anticonvulsants, clozapine [101]
• Hypereosinophilic syndrome (HES): idiopathic eosinophilia greater than 1,500/µL for greater than 6 months with organ damage [102]
• Churg-Strauss syndrome (EGPA): eosinophilic granulomatosis with polyangiitis [103]
• Parasitic infections: Toxocara, Trichinella, Echinococcus [104]

Pathophysiology:

• Eosinophil degranulation releases major basic protein (MBP), eosinophil cationic protein (ECP), eosinophil peroxidase (EPO) → direct myocardial toxicity [105]
• Three stages: acute necrotic, thrombotic, fibrotic [106]

Diagnosis:

• Peripheral eosinophilia (greater than 500/µL) in 70-90% [107]
• Endomyocardial biopsy: eosinophilic infiltration + myocyte necrosis [108]
• CMR: subendocardial LGE, apical thrombi [109]

Management:

• Remove offending agent (if drug-induced) [110]
• Corticosteroids: methylprednisolone 1 g/day × 3 days, then prednisone 1 mg/kg/day [111]
• Cytotoxic therapy for HES: hydroxyurea or imatinib (if FIP1L1-PDGFRA fusion positive) [112]

Cardiac Sarcoidosis

Epidemiology:

• Cardiac involvement in 20-30% of systemic sarcoidosis (clinical), 50-70% (autopsy studies) [113]
• Isolated cardiac sarcoidosis (no extracardiac involvement): 30-40% of cardiac sarcoid cases [114]

Pathology:

• Non-caseating granulomas in myocardium, conduction system, pericardium [115]
• Predilection for basal septum (AV node) and LV free wall [116]

Clinical Presentations:

• Conduction abnormalities (30-50%): AV block (most common), bundle branch blocks [117]
• Ventricular arrhythmias (25-40%): VT, VF, sudden cardiac death [118]
• Heart failure (25-35%): systolic or diastolic dysfunction [119]

Diagnosis (Heart Rhythm Society 2014 Criteria):

• Histological diagnosis: endomyocardial biopsy showing non-caseating granulomas (gold standard but low sensitivity 20-30% due to patchy distribution) [120]
• Clinical diagnosis (in patients with extracardiac sarcoidosis):
  • "One or more of: unexplained AV block, VT, LVEF below 40%, positive FDG-PET or CMR"
  • Exclusion of other causes [121]

Imaging:

• CMR: patchy LGE in non-ischaemic pattern (mid-wall, epicardial, especially basal septum); sensitivity 75-100% [122]
• FDG-PET: areas of increased glucose uptake (active inflammation); useful for monitoring treatment response [123]

Management:

• Immunosuppression: corticosteroids (prednisone 0.5-1 mg/kg/day) ± methotrexate or azathioprine for steroid-sparing [124]
• ICD: indicated for secondary prevention (aborted SCD, sustained VT) or primary prevention (LVEF below 35%, extensive LGE on CMR, inducible VT on EP study) [125]
• Pacemaker: for symptomatic bradycardia or high-grade AV block [126]

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Clinical Presentation

Acute Myocarditis

Presenting Symptoms:

• Chest pain (60-80%): pleuritic or pressure-like, may mimic ACS [127]
• Dyspnoea (40-60%): exertional or at rest; orthopnoea, PND [128]
• Palpitations (25-40%): due to arrhythmias [129]
• Syncope (5-15%): VT/VF or AV block [130]
• Fever (20-40%): often with viral prodrome (URTI, GI symptoms) [131]
• Fatigue (30-50%): non-specific but common [132]

Physical Examination:

• General: tachycardia (common), fever, respiratory distress
• Cardiovascular:
  • Tachycardia out of proportion to fever (may suggest myocarditis) [133]
  • S3 gallop (LV dysfunction) [134]
  • S4 gallop (reduced compliance) [135]
  • Murmurs of mitral or tricuspid regurgitation (ventricular dilatation) [136]
  • Pericardial rub (if associated pericarditis) [137]
  • Elevated JVP, peripheral oedema (right heart failure) [138]
• Respiratory: bibasal crackles (pulmonary oedema) [139]
• Extremities: cool peripheries, delayed capillary refill (cardiogenic shock) [140]

Fulminant Myocarditis

Defining Features (Lieberman Criteria):

1. Abrupt onset of symptoms (below 2 weeks from viral prodrome to presentation) [6]
2. Severe haemodynamic compromise requiring inotropes or mechanical support [6]
3. Severe LV dysfunction (EF below 35%) with ventricular dilatation [6]
4. Myocardial oedema on imaging [6]

Clinical Characteristics:

• Younger age (mean 35-42 years) compared to acute myocarditis (mean 45-52 years) [141]
• Female predominance (60% female) [6]
• Higher rates of cardiogenic shock (60-80% vs 5-10% in acute myocarditis) [142]
• More frequent arrhythmias (VT/VF 40-50%, AV block 30-40%) [143]
• Rapid progression: patients deteriorate within hours to days [144]

Haemodynamic Profile:

• Cardiac index below 2.2 L/min/m² [145]
• PCWP greater than 18 mmHg (often 20-30 mmHg) [146]
• SVR typically elevated (compensatory vasoconstriction) [147]
• Mixed venous oxygen saturation (SvO₂) below 60% (inadequate tissue oxygen delivery) [148]

Paradoxical Prognosis:

• If survive acute phase: 93% survival at 11 years [6]
• Mechanism of better long-term prognosis:
  • Minimal or no ventricular dilatation (preserved LV architecture) [149]
  • Extensive myocardial oedema is reversible (vs fibrosis in acute myocarditis) [150]
  • Younger age and robust immune response clear viral infection efficiently [151]
  • Complete recovery of LV function in 80-90% by 6 months [152]

Checkpoint Inhibitor Myocarditis

Time to Onset:

• Median: 30-45 days after therapy initiation [70]
• Range: 1 day to 18 months [153]
• Earlier onset with combination therapy (PD-1/PD-L1 + CTLA-4) [154]

Clinical Presentation:

• Cardiac symptoms (60-70%): dyspnoea, chest pain, palpitations [155]
• Conduction abnormalities (40-60%): AV block, LBBB, RBBB [71]
• Asymptomatic (20-30%): detected on routine troponin surveillance [156]
• Overlap syndromes:
  • "Myositis (40-60%): elevated CK, muscle weakness [157]"
  • "Myasthenia gravis (10-20%): diplopia, ptosis, bulbar symptoms [158]"
  • "Hepatitis (20-30%): elevated transaminases [159]"

Severity and Outcomes:

• Mortality: 25-50% even with aggressive treatment [11,12]
• Cardiogenic shock in 40-60% [160]
• Complete heart block in 30-40% [161]
• Fulminant presentation more common than in viral myocarditis [162]

Diagnostic Red Flags:

• New-onset fatigue or dyspnoea in patient on checkpoint inhibitor [163]
• Troponin rise (any elevation warrants investigation) [164]
• ECG: new conduction abnormalities or arrhythmias [165]
• Elevated CK (suggests myositis overlap) [166]

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Investigations

Cardiac Biomarkers

Troponin (Troponin I or T):

• Sensitivity: 95% for myocarditis [21]
• Magnitude: typically 10-100× upper limit of normal (ULN), but can exceed 100× ULN in fulminant cases [22]
• Kinetics differ from ACS:
  • "Slower rise: peak at 24-72 hours (vs 12-24h in STEMI) [167]"
  • "Prolonged elevation: remains elevated greater than 2 weeks (vs 7-10 days in STEMI) [168]"
• Prognostic value: magnitude correlates with extent of myocardial injury but NOT with short-term mortality [169]
• Serial monitoring: useful to track disease evolution and response to treatment [170]

BNP / NT-proBNP:

• Elevated in 70-90% of myocarditis patients [171]
• Reflects myocardial stretch, LV dysfunction, and elevated filling pressures [172]
• Prognostic value: NT-proBNP greater than 5,000 pg/mL associated with worse outcomes [173]
• Useful for monitoring response to treatment and volume status [174]

CK / CK-MB:

• Elevated in 60-70% [175]
• Less specific than troponin (skeletal muscle injury can elevate CK) [176]
• Elevation greater than 10× ULN suggests extensive myocardial necrosis [177]

Inflammatory Markers:

• ESR / CRP: elevated in 60-80%, non-specific [178]
• White cell count: leucocytosis in 30-50%, eosinophilia suggests eosinophilic myocarditis [179]
• Procalcitonin: usually normal (helps exclude bacterial infection/sepsis) [180]

Electrocardiography

Common ECG Findings:

Differentiation from STEMI:

Echocardiography

Transthoracic Echocardiography (TTE):

Systolic Function:

• LVEF: typically 20-40% in fulminant myocarditis, 40-55% in acute myocarditis [189]
• Regional wall motion abnormalities (50-70%): may mimic ischaemic pattern (LAD territory, inferior wall) or diffuse hypokinesis [49]
• Global longitudinal strain (GLS): reduced even when LVEF appears normal; early marker of dysfunction [190]

Diastolic Function:

• Restrictive filling pattern (E/A ratio greater than 2, short deceleration time below 120 ms) in severe cases [52]
• Elevated E/e' ratio (greater than 14) indicates elevated LV filling pressures [191]

Structural Findings:

• LV wall thickness: increased (myocardial oedema) or normal [192]
• LV dimensions: normal or mildly dilated in fulminant (vs dilated in acute myocarditis) [193]
• Pericardial effusion: present in 30-60% (usually small to moderate) [194]
• RV dysfunction: occurs in 30-40%, poor prognostic sign [195]

Valvular Assessment:

• Mitral regurgitation: functional MR due to LV dilatation and annular dilatation [196]
• Tricuspid regurgitation: allows estimation of RV systolic pressure [197]

Haemodynamic Assessment:

• Cardiac output: reduced in cardiogenic shock [198]
• IVC diameter and collapsibility: assesses volume status and RA pressure [199]

Limitations:

• Non-specific findings: cannot definitively diagnose myocarditis (echo changes similar to DCM, ischaemic cardiomyopathy) [200]
• Normal echo does NOT exclude myocarditis (10-15% have normal LVEF) [201]

Cardiac Magnetic Resonance (CMR)

Lake Louise Criteria (2009, updated 2018):

Non-invasive gold standard for diagnosing myocarditis. Diagnosis requires ≥1 T2-based criterion + ≥1 T1-based criterion:

T2-Based Criteria (Myocardial Oedema/Inflammation):

1. T2-weighted imaging:

   • Global or regional increase in myocardial signal intensity [7]
   • T2 signal intensity ratio (myocardium/skeletal muscle) greater than 2.0 [8]
   • Sensitivity: 67%, Specificity: 91% [202]

2. T2 mapping:

   • Elevated T2 relaxation time greater than 50-55 ms (1.5T) or greater than 60-65 ms (3T) [203]
   • More quantitative and reproducible than T2-weighted imaging [204]

T1-Based Criteria (Myocardial Injury/Fibrosis):

1. Early gadolinium enhancement (EGE):

   • Increased signal intensity ratio (myocardium/skeletal muscle) greater than 4.0 on early post-contrast images [7]
   • Reflects hyperaemia and capillary leak [205]
   • Less commonly used in modern protocols [206]

2. Late gadolinium enhancement (LGE):

   • Non-ischaemic pattern: mid-wall, epicardial, or patchy distribution (spares subendocardium) [207]
   • Common locations: lateral wall, inferolateral wall [208]
   • Present in 60-90% of myocarditis cases [209]
   • Correlates with fibrosis and worse prognosis [210]

3. T1 mapping:

   • Elevated native T1 relaxation time greater than 1,000-1,050 ms (1.5T) or greater than 1,200-1,250 ms (3T) [211]
   • Reflects oedema and fibrosis [212]

4. Extracellular volume (ECV):

   • Elevated ECV greater than 28-30% [213]
   • Reflects expansion of extracellular space (oedema, fibrosis) [214]

CMR Diagnostic Performance:

• Sensitivity: 67-88% (depends on timing; highest at 1-2 weeks) [8,215]
• Specificity: 91-96% [202,216]
• Accuracy increases when combining multiple parameters (T2 mapping + LGE + ECV) [217]

Prognostic Value:

• LGE presence: associated with increased risk of adverse events (death, transplant, arrhythmias) [210]
• LGE extent: greater than 20% of LV mass predicts worse outcomes [218]
• Mid-wall LGE: higher risk of ventricular arrhythmias than epicardial LGE [219]

Limitations:

• Requires stable patient (scan duration 45-60 minutes) [220]
• Contraindications: severe haemodynamic instability, arrhythmias, renal failure (GFR below 30 for gadolinium), metallic implants [221]
• Timing-dependent: sensitivity highest at 1-2 weeks; early (below 3 days) or late (greater than 6 weeks) scans may be falsely negative [222]

Endomyocardial Biopsy (EMB)

Indications (ESC 2013 Position Statement):

Class I (Recommended):

1. Fulminant heart failure below 2 weeks duration with haemodynamic compromise [223]
2. Acute heart failure (2 weeks to 3 months) with dilated LV and new arrhythmias/AV block or failure to respond to treatment within 1-2 weeks [224]
3. Suspected giant cell myocarditis or eosinophilic myocarditis (to guide immunosuppression) [225]

Class IIa (Should be considered): 4. Chronic heart failure (greater than 3 months) with suspected restrictive cardiomyopathy, sarcoidosis, or eosinophilic myocarditis [226] 5. Unexplained ventricular arrhythmias [227]

Class III (Not recommended): 6. Stable chronic heart failure with suspected myocarditis (low diagnostic yield and no treatment implications) [228]

Technique:

• Approach: right internal jugular vein (preferred) or femoral vein [229]
• Target: interventricular septum (RV side) to avoid perforation [230]
• Number of samples: minimum 4-6 samples (ideally 6-8) to reduce sampling error [231]
• Imaging guidance: fluoroscopy or echocardiography to avoid complications [232]

Histological Criteria (Dallas Criteria):

• Active myocarditis: lymphocytic infiltration (greater than 5 lymphocytes per high-power field) + myocyte necrosis or damage [9]
• Borderline myocarditis: inflammatory infiltrate without myocyte damage [233]
• No myocarditis: no inflammatory infiltrate [234]

Immunohistochemistry:

• Quantifies inflammatory cells: CD3+ T cells, CD68+ macrophages, CD45+ leucocytes [235]
• greater than 14 leucocytes/mm² (CD45+) indicates active inflammation [236]

Viral PCR:

• Detects viral genomes in myocardial tissue [237]
• greater than 500 copies/µg DNA suggests active viral replication [69]
• Common viruses: parvovirus B19, HHV-6, enteroviruses, adenovirus [60-63]

Diagnostic Performance:

• Sensitivity: 10-35% (low due to patchy distribution of inflammation) [10,238]
• Specificity: 80-95% when Dallas criteria met [239]
• Yield improves with more samples (6-8 vs 3-4) and targeting inflamed areas on CMR [240]

Complications:

• Overall complication rate: 3-6% [241]
• Perforation with tamponade: 0.5-1% [242]
• Arrhythmias (VT, complete heart block): 1-2% [243]
• Tricuspid regurgitation: 1-2% [244]
• Death: below 0.5% [245]

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Management

Initial Resuscitation and Supportive Care

ABCDE Approach:

A. Airway:

• Protect airway if GCS below 8 or respiratory failure [246]
• Rapid sequence intubation with induction agents titrated to haemodynamics (ketamine 1-2 mg/kg preferred in shock) [247]

B. Breathing:

• Oxygen to maintain SpO₂ ≥94% (avoid hyperoxia) [248]
• Non-invasive ventilation (CPAP/BiPAP) for pulmonary oedema if haemodynamically stable [249]
• Mechanical ventilation: low tidal volume (6-8 mL/kg IBW), minimise PEEP to reduce RV afterload [250]

C. Circulation:

• IV access: two large-bore peripheral cannulae + consider central venous access [251]
• Fluid resuscitation: cautious crystalloid boluses (250-500 mL) if hypovolaemic; AVOID aggressive fluids (worsens pulmonary oedema) [252]
• Vasopressors/Inotropes (if cardiogenic shock):
  • "Noradrenaline 0.05-0.5 µg/kg/min: first-line vasopressor for hypotension (SBP below 90 mmHg) to maintain MAP ≥65 mmHg [253]"
  • "Dobutamine 2.5-20 µg/kg/min: inotrope for low cardiac output (CI below 2.2 L/min/m²) [254]"
  • "Milrinone 0.25-0.75 µg/kg/min: phosphodiesterase-3 inhibitor; inotrope + vasodilator (reduces SVR and afterload); useful in RV failure [255]"
  • "Adrenaline 0.05-0.5 µg/kg/min: reserve for refractory shock; risk of tachyarrhythmias [256]"
  • "Levosimendan 0.05-0.2 µg/kg/min: calcium sensitiser + vasodilator; may be superior to dobutamine but limited availability [257]"

D. Disability:

• GCS assessment; altered mental status suggests hypoperfusion [258]

E. Exposure:

• Core temperature; fever suggests viral aetiology or drug reaction [259]

Haemodynamic Monitoring:

• Arterial line: continuous BP monitoring, serial ABGs [260]
• Central venous pressure (CVP): assess preload (target 8-12 mmHg) [261]
• Pulmonary artery catheter (PAC): consider in refractory shock to guide therapy:
  • Cardiac index (CI), PCWP, SVR, mixed venous oxygen saturation (SvO₂) [262]
  • "Classic profile: CI below 2.2 L/min/m², PCWP greater than 18 mmHg, SVR elevated [263]"
• Transthoracic echocardiography: assess LV/RV function, valves, pericardial effusion, guide fluid and inotrope therapy [264]

Medical Management

Heart Failure Therapy:

Acute Phase (Haemodynamically Unstable):

• Diuretics: furosemide 20-80 mg IV bolus or infusion (5-10 mg/h) to reduce pulmonary congestion [265]
• Vasodilators (if SBP greater than 100 mmHg): glyceryl trinitrate (GTN) 10-200 µg/min IV to reduce preload and afterload [266]
• AVOID ACE inhibitors / ARBs / beta-blockers in acute unstable phase (risk of worsening hypotension) [267]

Stabilisation Phase (Haemodynamically Stable):

• ACE inhibitors or ARBs:
  • Start when stable (SBP greater than 100 mmHg, off/minimal inotropes) [268]
  • Ramipril 1.25-2.5 mg daily, titrate to target 10 mg daily [269]
  • Enalapril 2.5 mg BD, titrate to 10-20 mg BD [270]
  • Reduces mortality and progression to DCM [271]
• Beta-blockers:
  • Start after ACE inhibitor, once euvolaemic and haemodynamically stable [272]
  • Bisoprolol 1.25 mg daily, titrate to 10 mg daily [273]
  • Carvedilol 3.125 mg BD, titrate to 25-50 mg BD [274]
  • AVOID in acute phase (negative inotropy, worsens shock) [275]
  • Beta-blockers may reduce viral replication by decreasing cAMP [276]
• Mineralocorticoid receptor antagonists (MRA):
  • Spironolactone 25 mg daily or eplerenone 25 mg daily [277]
  • Monitor potassium (avoid if K⁺ greater than 5.0 mmol/L or CrCl below 30 mL/min) [278]
• SGLT2 inhibitors (in chronic phase):
  • Dapagliflozin 10 mg daily or empagliflozin 10 mg daily [279]
  • Emerging evidence for benefit in non-ischaemic cardiomyopathy [280]

Arrhythmia Management:

Ventricular Arrhythmias (VT/VF):

• Sustained VT with pulse: amiodarone 150 mg IV over 10 min, then infusion 1 mg/min × 6h, then 0.5 mg/min [281]
• VT/VF cardiac arrest: defibrillation as per ALS protocol; adrenaline 1 mg IV every 3-5 min; amiodarone 300 mg IV after 3rd shock [282]
• Refractory VT: lidocaine 1-1.5 mg/kg IV bolus, then infusion 1-4 mg/min [283]
• Electrical storm (≥3 VT/VF episodes in 24h): deep sedation, beta-blockers (if haemodynamically tolerated), consider ECMO [284]
• Long-term: wearable cardioverter-defibrillator (WCD) for 3-6 months; permanent ICD if persistent LVEF below 35% after 6 months [285]

Bradyarrhythmias and AV Blocks:

• Symptomatic bradycardia: atropine 0.6-1.2 mg IV (may be ineffective in AV nodal block) [286]
• 2° AV block (Mobitz II) or 3° AV block:
  • "Temporary pacing: transcutaneous or transvenous [287]"
  • "Indication for temporary pacing: haemodynamic instability, syncope, escape rhythm below 40 bpm [288]"
  • Most AV blocks resolve within 2-4 weeks (viral myocarditis) [289]
  • "Permanent pacing: consider if block persists greater than 2 weeks or in giant cell/sarcoid myocarditis [290]"

Atrial Fibrillation:

• Rate control: beta-blockers (if stable) or digoxin 0.5 mg IV loading, then 0.125-0.25 mg daily [291]
• Anticoagulation: therapeutic anticoagulation (heparin or DOAC) if AF greater than 48h or LVEF below 35% [292]

Anticoagulation:

Indications:

• LVEF below 30-35%: risk of LV thrombus [293]
• Atrial fibrillation: CHA₂DS₂-VASc score [294]
• LV thrombus on echo/CMR: therapeutic anticoagulation (warfarin INR 2-3 or DOAC) [295]
• Giant cell or eosinophilic myocarditis: high risk of mural thrombi [296]

Agents:

• Heparin (UFH or LMWH) acutely, transition to warfarin or DOAC (apixaban, rivaroxaban) [297]
• Duration: minimum 3-6 months, continue if thrombus persists or LVEF remains below 35% [298]

Immunosuppression:

CRITICAL: Immunosuppression is NOT routine and can be harmful in viral myocarditis [19,20]

Indications for Immunosuppression:

1. Giant cell myocarditis (biopsy-proven):

   • Regimen: prednisone 1 mg/kg/day (or methylprednisolone 1 g IV daily × 3 days) + cyclosporine 3-5 mg/kg/day (target trough 150-250 ng/mL) OR tacrolimus 0.05-0.1 mg/kg/day (target trough 8-12 ng/mL) + azathioprine 2 mg/kg/day OR mycophenolate 1-1.5 g BD [97,98]
   • Duration: 6-12 months minimum [299]
   • Monitor: FBC (leucopenia, thrombocytopenia), LFTs, renal function, cyclosporine/tacrolimus levels [300]

2. Eosinophilic myocarditis (biopsy-proven or high clinical suspicion):

   • Regimen: methylprednisolone 1 g IV daily × 3 days, then prednisone 1 mg/kg/day [111]
   • Taper over 6-12 months based on response [301]
   • Add cytotoxic therapy (hydroxyurea, imatinib) for hypereosinophilic syndrome [112]

3. Cardiac sarcoidosis:

   • Regimen: prednisone 0.5-1 mg/kg/day (30-60 mg daily) [124]
   • Taper to maintenance 5-10 mg daily over 6-12 months [302]
   • Steroid-sparing agents: methotrexate 10-25 mg weekly, azathioprine 2 mg/kg/day [303]
   • Monitor response: serial CMR or FDG-PET [304]

4. Checkpoint inhibitor myocarditis:

   • Regimen: methylprednisolone 500-1,000 mg IV daily × 3 days, then prednisone 1-2 mg/kg/day [73]
   • Immediate cessation of checkpoint inhibitor [305]
   • Refractory cases: infliximab 5 mg/kg IV or IVIG 2 g/kg or abatacept [306]
   • Consider mycophenolate or tacrolimus for steroid-refractory cases [307]

5. Autoimmune myocarditis (biopsy-proven, no viral PCR):

   • Regimen: corticosteroids ± immunosuppressant (case-by-case basis) [308]

Contraindications to Immunosuppression:

• Viral myocarditis with positive viral PCR (increases viral replication, worsens outcomes) [19,20]
• Active systemic infection [309]
• Uncontrolled diabetes [310]

Mechanical Circulatory Support (MCS)

Indications for MCS:

• Cardiogenic shock refractory to medical therapy (inotropes/vasopressors at moderate-high doses) [311]
• Haemodynamic criteria:
  • SBP below 90 mmHg despite inotropes [312]
  • Cardiac index below 2.0 L/min/m² [313]
  • Lactate greater than 2.5 mmol/L (tissue hypoperfusion) [314]
  • Rising creatinine (renal hypoperfusion) [315]
• Progressive end-organ dysfunction: oliguria, altered mental status, liver dysfunction [316]
• Bridge to recovery (most common in fulminant myocarditis) or bridge to transplant [317]

MCS Modalities:

VA-ECMO in Fulminant Myocarditis:

Cannulation Strategy:

• Peripheral VA-ECMO: femoral vein (drainage) + femoral artery (return) [318]
• Central VA-ECMO: right atrium (drainage) + ascending aorta (return); requires sternotomy [319]
• Distal perfusion cannula: recommended for femoral arterial cannulation to prevent limb ischaemia [320]

Haemodynamic Effects:

• Increases systemic perfusion but increases LV afterload (retrograde aortic flow) [321]
• Risk of LV distension → pulmonary oedema, ventricular thrombus, subendocardial ischaemia [322]
• LV venting strategies:
  • Impella + VA-ECMO ("ECMELLA" configuration) [323]
  • Atrial septostomy [324]
  • Percutaneous LV vent catheter [325]

Outcomes:

• Survival to discharge: 60-75% in fulminant myocarditis [15,16]
• Duration of support: median 4-7 days (range 1-30+ days) [326]
• Weaning trials: typically after 48-72 hours if haemodynamics improving and LV function recovering [327]

Complications:

• Bleeding: most common (30-50%), requiring transfusion [328]
• Limb ischaemia: 10-25%, requires distal perfusion cannula or fasciotomy [329]
• Stroke: 5-15% (haemorrhagic or ischaemic) [330]
• Infection: 15-30% (cannula site, bloodstream, pneumonia) [331]
• Haemolysis: 5-15%, especially with Impella [332]
• Renal failure: 30-50%, may require renal replacement therapy (RRT) [333]
• Harlequin syndrome (differential hypoxia): upper body cyanosis in peripheral VA-ECMO if native cardiac function ejects deoxygenated blood [334]

Weaning from VA-ECMO:

• Criteria: LVEF greater than 35-40%, minimal inotrope support, resolving myocardial oedema on echo [335]
• Weaning trial: reduce ECMO flow to 1-2 L/min for 30-60 min, assess haemodynamics [336]
• Decannulation: if trial successful and no haemodynamic deterioration [337]

Transplantation

Indications for Cardiac Transplant Listing:

• Giant cell myocarditis: early listing due to poor prognosis without transplant [99]
• Refractory cardiogenic shock requiring prolonged MCS (greater than 2-4 weeks) without LV recovery [338]
• Progression to end-stage dilated cardiomyopathy (LVEF below 20-25%, NYHA Class IV, recurrent hospitalisations) [339]

Outcomes Post-Transplant:

• Giant cell myocarditis: 5-year survival 71% post-transplant [99]
• Recurrence of giant cell myocarditis in allograft: 10-25% (requires ongoing immunosuppression) [340]

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Prognosis and Long-Term Follow-Up

Acute Phase Prognosis

Mortality Predictors:

• Fulminant presentation (paradoxically better long-term if survive acute phase) [6]
• Giant cell histology (89% mortality at 5.5 years without transplant) [13]
• Checkpoint inhibitor aetiology (25-50% mortality) [11,12]
• Syncope at presentation (suggests arrhythmia) [341]
• NYHA Class IV symptoms [342]
• Requirement for mechanical circulatory support [343]
• Multiorgan failure (renal, hepatic, respiratory) [344]
• Elevated lactate greater than 4 mmol/L (tissue hypoperfusion) [345]

Long-Term Outcomes

LV Function Recovery:

• Fulminant myocarditis: 80-90% achieve complete or near-complete recovery (LVEF greater than 50%) by 6 months [152]
• Acute (non-fulminant) myocarditis: 45% develop persistent LV dysfunction, 12% progress to DCM [33]
• Viral myocarditis: 50-70% recover to LVEF greater than 50% within 1 year [346]

Progression to Dilated Cardiomyopathy (DCM):

• Risk factors: persistent viral infection (PCR+), extensive LGE on CMR (greater than 20% LV mass), older age, male gender [347]
• Time to DCM: median 2-5 years [348]

Arrhythmia Risk:

• Ventricular arrhythmias: persist in 10-20% despite LV function recovery [349]
• Risk factors: extensive LGE (especially mid-wall), LVEF below 35%, inducible VT on EP study [350]

Sudden Cardiac Death:

• Risk: 1-3% per year in recovered myocarditis [351]
• Wearable cardioverter-defibrillator (WCD) for first 3-6 months [352]
• Permanent ICD if LVEF below 35% after 6 months of optimal medical therapy [353]

Follow-Up Strategy

Acute Phase (0-3 months):

• Weekly: clinical assessment, ECG, troponin, BNP [354]
• 2-4 weeks: repeat TTE to assess LV function recovery [355]
• 6-8 weeks: repeat CMR (if initial LGE present) to assess resolution of oedema/inflammation [356]

Chronic Phase (3-12 months):

• Monthly: clinical review, titrate heart failure medications [357]
• 3 months: TTE, consider CMR if LV dysfunction persists [358]
• 6 months: TTE, ECG, Holter monitor (if arrhythmias), BNP [359]
• 6 months: ICD decision if LVEF below 35% despite optimal therapy [360]

Long-Term (greater than 12 months):

• 6-12 monthly: clinical review, TTE, ECG, BNP [361]
• CMR: every 1-2 years if LGE present or LV dysfunction [362]
• Exercise restriction: avoid competitive sports for 6 months; return to sport only if LVEF greater than 50%, no arrhythmias, no LGE [363]

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SAQ Practice Questions

SAQ 1: Fulminant vs Acute Myocarditis

Question: A 28-year-old female presents with 5 days of progressive dyspnoea and chest pain. She had a viral illness 1 week ago. On examination: BP 85/60 mmHg, HR 130 bpm, cold peripheries, bibasal crackles. ECG shows sinus tachycardia with diffuse ST elevation. Troponin 78 ng/mL (normal below 14). TTE: LVEF 25%, global hypokinesis, normal LV dimensions, no dilatation.

(a) Define fulminant myocarditis and explain how this differs from acute myocarditis. (4 marks) (b) Outline the paradoxical prognostic difference between fulminant and acute myocarditis. (3 marks) (c) List the indications for mechanical circulatory support in this patient. (3 marks)

Model Answer:

(a) Fulminant myocarditis definition and distinction from acute myocarditis (4 marks):

Fulminant myocarditis (Lieberman criteria):

• Abrupt onset of symptoms below 2 weeks from viral prodrome (1 mark)
• Severe haemodynamic compromise requiring inotropes/vasopressors or mechanical circulatory support (1 mark)
• Severe LV dysfunction (EF below 35%) without significant ventricular dilatation (1 mark)

Acute (non-fulminant) myocarditis:

• Subacute onset over weeks to months
• Less severe haemodynamic compromise (stable or mild heart failure)
• Variable LV dysfunction (EF 30-50%) with ventricular dilatation
• May be asymptomatic or have mild symptoms (1 mark)

(b) Paradoxical prognostic difference (3 marks):

Fulminant myocarditis (better long-term prognosis IF survive acute phase):

• 93% survival at 11 years for those who survive initial hospitalisation (1 mark)
• 80-90% achieve complete or near-complete recovery of LV function (LVEF greater than 50%) by 6 months (1 mark)
• Mechanism: minimal ventricular dilatation preserves LV architecture; extensive myocardial oedema is reversible (vs fibrosis in acute myocarditis); younger patients with robust immune response clear virus efficiently (1 mark)

Acute (non-fulminant) myocarditis (worse long-term prognosis):

• 45% develop persistent LV dysfunction, 12% progress to dilated cardiomyopathy
• Mechanism: ventricular dilatation, chronic inflammation, myocardial fibrosis

(c) Indications for mechanical circulatory support (3 marks):

• Cardiogenic shock refractory to medical therapy (inotropes/vasopressors at moderate-high doses) with SBP below 90 mmHg despite treatment (1 mark)
• Haemodynamic criteria: cardiac index below 2.0 L/min/m², lactate greater than 2.5 mmol/L, rising creatinine (1 mark)
• Progressive end-organ dysfunction: oliguria, altered mental status, liver dysfunction despite maximal medical therapy (1 mark)

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SAQ 2: CMR Lake Louise Criteria

Question: A 35-year-old male presents with chest pain and dyspnoea 1 week after a viral illness. Troponin 45 ng/mL. TTE: LVEF 40%, no regional wall motion abnormalities. CMR is performed.

(a) Describe the Lake Louise criteria for diagnosing myocarditis on CMR. (5 marks) (b) Explain the prognostic significance of late gadolinium enhancement (LGE) in myocarditis. (3 marks) (c) List the limitations of CMR in diagnosing myocarditis. (2 marks)

Model Answer:

(a) Lake Louise criteria (5 marks):

Diagnosis requires ≥1 T2-based criterion + ≥1 T1-based criterion:

T2-based criteria (myocardial oedema/inflammation):

• T2-weighted imaging: global or regional increase in myocardial signal intensity; T2 signal intensity ratio (myocardium/skeletal muscle) greater than 2.0 (1 mark)
• T2 mapping: elevated T2 relaxation time greater than 50-55 ms (1.5T) or greater than 60-65 ms (3T) (1 mark)

T1-based criteria (myocardial injury/fibrosis):

• Late gadolinium enhancement (LGE): non-ischaemic pattern (mid-wall, epicardial, or patchy distribution, spares subendocardium); common locations are lateral and inferolateral walls (1 mark)
• T1 mapping: elevated native T1 relaxation time greater than 1,000-1,050 ms (1.5T) or greater than 1,200-1,250 ms (3T) (1 mark)
• Extracellular volume (ECV): elevated ECV greater than 28-30%, reflects expansion of extracellular space (oedema, fibrosis) (1 mark)

(b) Prognostic significance of LGE (3 marks):

• Presence of LGE associates with increased risk of adverse events: death, heart transplant, ventricular arrhythmias, progression to dilated cardiomyopathy (1 mark)
• Extent of LGE greater than 20% of LV mass predicts worse outcomes and higher risk of heart failure progression (1 mark)
• Pattern of LGE: mid-wall LGE has higher risk of ventricular arrhythmias than epicardial LGE; LGE reflects irreversible myocardial fibrosis (1 mark)

(c) Limitations of CMR (2 marks):

• Timing-dependent: sensitivity highest at 1-2 weeks after symptom onset; early (below 3 days) or late (greater than 6 weeks) scans may be falsely negative (1 mark)
• Patient-related limitations: requires stable haemodynamics (scan duration 45-60 min); contraindications include severe haemodynamic instability, arrhythmias, renal failure (GFR below 30 for gadolinium), metallic implants (pacemakers, ICDs unless MR-conditional) (1 mark)

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SAQ 3: Checkpoint Inhibitor Myocarditis

Question: A 62-year-old male with metastatic melanoma on pembrolizumab (PD-1 inhibitor) presents 6 weeks after starting therapy with fatigue and dyspnoea. ECG shows new LBBB. Troponin 38 ng/mL. CK 2,400 U/L (elevated). TTE: LVEF 35%, global hypokinesis.

(a) What is the most likely diagnosis? Justify your answer. (3 marks) (b) Outline the immediate management of this patient. (4 marks) (c) Describe the prognosis of this condition. (3 marks)

Model Answer:

(a) Most likely diagnosis (3 marks):

Checkpoint inhibitor myocarditis (with myositis overlap) (1 mark)

Justification:

• Temporal relationship: presentation 6 weeks after pembrolizumab initiation (median onset 30-45 days) (1 mark)
• Characteristic features: new conduction abnormality (LBBB), elevated troponin, elevated CK (suggests myositis overlap which occurs in 40-60% of checkpoint inhibitor myocarditis), LV dysfunction (1 mark)

(b) Immediate management (4 marks):

1. Immediate cessation of pembrolizumab (1 mark)

2. High-dose corticosteroids: methylprednisolone 500-1,000 mg IV daily for 3 days, then prednisone 1-2 mg/kg/day (1 mark)

3. Cardiac monitoring: telemetry for arrhythmias and progression of AV block; temporary pacing if high-grade AV block develops (1 mark)

4. Supportive cardiac care: standard heart failure therapy (diuretics, ACE inhibitors, beta-blockers) once haemodynamically stable; consider mechanical circulatory support (IABP, Impella, VA-ECMO) if cardiogenic shock (1 mark)

5. Second-line immunosuppression (if refractory to corticosteroids): infliximab 5 mg/kg IV, IVIG 2 g/kg over 2-5 days, or mycophenolate/tacrolimus

(c) Prognosis (3 marks):

• Mortality: 25-50% despite aggressive immunosuppression treatment (1 mark)
• Severity: 40-60% develop cardiogenic shock; 30-40% develop complete heart block requiring pacing (1 mark)
• Fulminant course: checkpoint inhibitor myocarditis is more likely to present in a fulminant fashion compared to viral myocarditis; high-risk features include combination immunotherapy (PD-1/PD-L1 + CTLA-4), myositis overlap, delay in diagnosis (1 mark)

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SAQ 4: Giant Cell Myocarditis

Question: A 45-year-old woman with ulcerative colitis presents with 2 weeks of progressive dyspnoea and palpitations. TTE: LVEF 20%, dilated LV. ECG shows frequent PVCs and runs of VT. Endomyocardial biopsy shows multinucleated giant cells and diffuse lymphocytic infiltration without granulomas. Viral PCR negative.

(a) What is the diagnosis? (1 mark) (b) Describe the prognosis of this condition if untreated. (2 marks) (c) Outline the management strategy. (7 marks)

Model Answer:

(a) Diagnosis (1 mark):

Giant cell myocarditis (1 mark)

(b) Prognosis if untreated (2 marks):

• Rapidly progressive disease: median survival 3-6 months without treatment (1 mark)
• 89% mortality at 5.5 years without cardiac transplantation; transplant-free survival is extremely poor (1 mark)

(c) Management strategy (7 marks):

Immunosuppression (1 mark):

• Triple-agent regimen:
  • "Corticosteroids: prednisone 1 mg/kg/day (60-80 mg/day) OR methylprednisolone 1 g IV daily × 3 days (1 mark)"
  • "Calcineurin inhibitor: cyclosporine 3-5 mg/kg/day (target trough 150-250 ng/mL) OR tacrolimus 0.05-0.1 mg/kg/day (target trough 8-12 ng/mL) (1 mark)"
  • "Antimetabolite: azathioprine 2 mg/kg/day OR mycophenolate 1-1.5 g BD (1 mark)"
• Duration: minimum 6-12 months

Cardiac transplant referral (1 mark):

• Early listing due to poor prognosis without transplant
• 5-year survival post-transplant: 71%
• Risk of recurrence in allograft: 10-25%

Arrhythmia management (1 mark):

• Amiodarone for ventricular arrhythmias
• Wearable cardioverter-defibrillator (WCD) or ICD for secondary prevention
• Consider catheter ablation for refractory VT

Mechanical circulatory support (1 mark):

• IABP, Impella, or VA-ECMO as bridge to transplant if cardiogenic shock
• BiVAD or total artificial heart if prolonged support required

Monitoring:

• Serial echocardiography, arrhythmia surveillance (Holter, telemetry)
• Monitor immunosuppression levels, side effects (infection, renal dysfunction, bone marrow suppression)

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Viva Voce Scenarios

Viva 1: Fulminant Myocarditis in Cardiogenic Shock

Scenario: You are the ICU registrar. A 32-year-old previously healthy female is transferred from the emergency department. She presented with 3 days of chest pain and dyspnoea following a viral illness. In ED, she became hypotensive (BP 75/50 mmHg) despite fluid resuscitation. Examination: HR 140 bpm, cold clammy peripheries, bibasal crackles, elevated JVP. ECG shows diffuse ST elevation and PR depression. Troponin 95 ng/mL. TTE: LVEF 22%, global hypokinesis, no ventricular dilatation, small pericardial effusion.

She is on noradrenaline 0.15 µg/kg/min and dobutamine 10 µg/kg/min, but SBP remains 80-85 mmHg. Lactate 3.8 mmol/L. Urine output 15 mL/hour over last 2 hours.

Question 1: What is your differential diagnosis? (2 min)

Model Answer:

Most likely diagnosis: Fulminant viral myocarditis (meets Lieberman criteria: abrupt onset below 2 weeks, severe haemodynamic compromise, severe LV dysfunction EF below 35% without dilatation)

Differentials:

1. Acute coronary syndrome (STEMI): diffuse ST elevation and PR depression favour myopericarditis over STEMI; young age, no cardiovascular risk factors make ACS less likely; requires urgent coronary angiography to exclude
2. Takotsubo cardiomyopathy: typically post-menopausal women, apical ballooning on echo; can have similar presentation
3. Acute viral pericarditis with myocardial involvement (myopericarditis): pericardial effusion present but small; clinical features suggest predominant myocardial involvement
4. Septic shock with myocardial depression: possible but fever/leucocytosis details not provided; troponin elevation very high for sepsis-induced cardiomyopathy

Investigations to differentiate:

• Coronary angiography: exclude ACS (should show normal coronary arteries in myocarditis)
• CMR (when stable): Lake Louise criteria for myocarditis; LGE pattern (non-ischaemic vs ischaemic)
• Endomyocardial biopsy: consider if diagnosis unclear or not responding to supportive care

Question 2: Outline your initial management priorities. (3 min)

Model Answer:

A. Immediate Resuscitation:

1. Airway and Breathing:

   • Consider intubation if work of breathing excessive or worsening mental status
   • Induction agent: ketamine 1-2 mg/kg (maintains haemodynamics)
   • Mechanical ventilation: low tidal volume 6-8 mL/kg, minimise PEEP to avoid further RV compromise

2. Circulation:

   • Vasopressor/inotrope optimisation:
     • Continue noradrenaline (target MAP ≥65 mmHg)
     • Dobutamine dose adequate (10 µg/kg/min); can increase to 20 µg/kg/min if needed
     • Consider adding milrinone 0.25-0.5 µg/kg/min (PDE3 inhibitor: inotrope + afterload reduction)
   • Haemodynamic monitoring:
     • Arterial line for continuous BP monitoring
     • Central venous catheter for CVP monitoring, vasopressor delivery
     • Consider pulmonary artery catheter (PAC) to guide therapy: assess CI, PCWP, SVR
     • Serial echocardiography to assess cardiac function and response
   • Fluid management:
     • AVOID aggressive fluids (worsens pulmonary oedema)
     • Cautious 250 mL boluses ONLY if CVP low and echo suggests hypovolaemia

3. Diuresis:

   • Furosemide 40-80 mg IV to reduce pulmonary congestion and improve oxygenation
   • Monitor urine output, electrolytes

B. Definitive Investigations:

• Urgent coronary angiography: exclude STEMI (if cath lab available immediately)
• Blood tests: FBC, UEC, LFTs, coagulation, CRP, viral serology, blood cultures
• Repeat ECG and troponin: track changes
• Arterial blood gas: assess acidosis, lactate

C. Mechanical Circulatory Support Decision:

Indications for MCS: YES – patient meets criteria

• SBP below 90 mmHg despite moderate-high dose inotropes/vasopressors
• Lactate greater than 2.5 mmol/L (tissue hypoperfusion)
• Oliguria (renal hypoperfusion)
• Cardiac index likely below 2.0 L/min/m² (based on clinical picture)

MCS options:

1. VA-ECMO (preferred for fulminant myocarditis):

   • Full cardiopulmonary support (flow 3-7 L/min)
   • Rapid deployment (percutaneous femoral cannulation)
   • Bridge to recovery (most common in fulminant myocarditis)
   • Survival 60-75% in contemporary series
   • Cannulation: femoral vein (drainage) + femoral artery (return) + distal perfusion cannula (prevent limb ischaemia)

2. Impella (alternative or adjunct):

   • Direct LV unloading (prevents LV distension on VA-ECMO)
   • Flow 2.5-5.5 L/min (device-dependent)
   • Can combine with VA-ECMO ("ECMELLA" configuration)

Decision: Urgent cardiothoracic/ECMO team discussion for VA-ECMO insertion

D. Multidisciplinary Involvement:

• Cardiology/Cardiothoracic surgery consultation
• ECMO team activation
• Cardiac transplant team discussion (in case progression to transplant needed)

Question 3: She is supported on VA-ECMO for 6 days and successfully weaned. What is her long-term prognosis? (2 min)

Model Answer:

Excellent long-term prognosis for fulminant myocarditis survivors:

1. Survival: 93% survival at 11 years (if survive acute hospitalisation) – better than acute non-fulminant myocarditis

2. LV function recovery: 80-90% achieve complete or near-complete recovery (LVEF greater than 50%) by 6 months

3. Mechanism of favourable prognosis:

   • Minimal ventricular dilatation preserves LV architecture
   • Extensive myocardial oedema is reversible (vs fibrosis in acute myocarditis)
   • Young age and robust immune response clear viral infection efficiently

4. Follow-up strategy:

   • 2-4 weeks: repeat TTE to assess LV function recovery
   • 6-8 weeks: CMR to assess resolution of oedema/inflammation, detect LGE (fibrosis)
   • 3 months: TTE, Holter monitor (arrhythmia surveillance), optimise heart failure medications (ACE-I, beta-blocker)
   • 6 months: reassess LVEF; if below 35%, consider ICD for primary prevention; if greater than 50% and no arrhythmias, can consider return to normal activities
   • Exercise restriction: avoid competitive sports for 6 months minimum

5. Arrhythmia risk:

   • Wearable cardioverter-defibrillator (WCD) for first 3-6 months
   • Permanent ICD if LVEF below 35% at 6 months or persistent ventricular arrhythmias
   • Most AV blocks (if present) resolve within 2-4 weeks

6. Risk of progression to DCM: very low in fulminant myocarditis (vs 12% in acute myocarditis)

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Viva 2: Checkpoint Inhibitor Myocarditis

Scenario: A 58-year-old male with non-small cell lung cancer on nivolumab (PD-1 inhibitor) presents 4 weeks after starting therapy. He complains of fatigue, muscle weakness, and dyspnoea. ECG shows new 2:1 AV block. Troponin 42 ng/mL. CK 3,800 U/L. TTE: LVEF 30%.

Question 1: What is your diagnosis and differential? (2 min)

Model Answer:

Primary diagnosis: Checkpoint inhibitor myocarditis with myositis overlap

Justification:

• Temporal relationship: 4 weeks after nivolumab (median onset 30-45 days)
• Cardiac: elevated troponin, new conduction abnormality (2:1 AV block – common in checkpoint inhibitor myocarditis), LV dysfunction
• Myositis: elevated CK, muscle weakness (40-60% of checkpoint inhibitor myocarditis has myositis overlap)

Differentials:

1. Isolated myocarditis (viral or other): less likely given elevated CK and muscle weakness; temporal relationship with checkpoint inhibitor strongest clue
2. Isolated myositis: CK elevation fits, but troponin elevation and AV block suggest cardiac involvement
3. Acute coronary syndrome: possible but less likely in absence of chest pain, younger age; ECG shows AV block not typical ischaemic changes
4. Myasthenia gravis (another checkpoint inhibitor toxicity): can present with muscle weakness but wouldn't cause elevated CK or cardiac involvement

Investigations:

• Cardiac: serial troponin, ECG (monitor AV block progression), CMR (Lake Louise criteria, LGE), consider endomyocardial biopsy if diagnosis uncertain
• Myositis: CK, aldolase, muscle biopsy (if diagnosis uncertain)
• Exclude other causes: viral serology, autoimmune screen (ANA, anti-Jo-1 antibodies)

Question 2: Outline your management. (3 min)

Model Answer:

1. Immediate Cessation of Nivolumab (CRITICAL)

• Permanent discontinuation
• Discuss with oncology team regarding cancer management alternatives

2. High-Dose Corticosteroids:

• Methylprednisolone 500-1,000 mg IV daily × 3 days
• Then taper to oral prednisone 1-2 mg/kg/day (60-120 mg/day)
• Gradual taper over 4-6 weeks based on clinical response, troponin trend, CK normalisation

3. Cardiac Monitoring and Support:

• Telemetry: monitor for progression to complete heart block
• Temporary pacing:
  • "Indications: haemodynamic instability, syncope, progression to complete heart block, symptomatic bradycardia"
  • "Route: transcutaneous (immediate) or transvenous (if prolonged)"
• Heart failure management:
  • Diuretics (furosemide) for volume overload
  • ACE inhibitors, beta-blockers (once haemodynamically stable)
  • Inotropes (dobutamine, milrinone) if cardiogenic shock
  • Mechanical circulatory support (IABP, Impella, VA-ECMO) if refractory shock

4. Second-Line Immunosuppression (if refractory to corticosteroids after 48-72h):

• Infliximab 5 mg/kg IV (anti-TNFα monoclonal antibody)
  • Screen for latent TB before administration
• IVIG 2 g/kg IV over 2-5 days
• Abatacept (CTLA-4 agonist, blocks T-cell activation)
• Mycophenolate or tacrolimus for steroid-refractory cases

5. Myositis Management:

• Corticosteroids treat both myocarditis and myositis
• Monitor CK trend (should fall with treatment)
• Physiotherapy to maintain muscle strength

6. Monitoring:

• Daily: ECG, troponin, CK, clinical status
• Serial TTE (every 1-2 weeks) to assess LV function recovery
• CMR (at 4-6 weeks) to assess extent of injury and response

7. Multidisciplinary Team:

• Cardiology, oncology, immunology, rheumatology, ICU

Question 3: What is the prognosis? (1 min)

Model Answer:

Poor prognosis despite aggressive treatment:

1. Mortality: 25-50% even with immunosuppression (much worse than viral myocarditis)

2. Severity:

   • 40-60% develop cardiogenic shock
   • 30-40% develop complete heart block
   • Often fulminant presentation

3. Predictors of worse outcome:

   • Combination immunotherapy (PD-1/PD-L1 + CTLA-4): higher mortality
   • Myositis overlap: higher CK correlates with worse cardiac outcomes
   • Delayed diagnosis/treatment: early recognition and immediate corticosteroids improve survival
   • Troponin greater than 50× ULN: marker of extensive myocardial injury

4. Recovery (if survive acute phase):

   • Variable LV function recovery
   • May require permanent pacing for persistent AV block
   • Long-term immunosuppression may be needed

5. Oncological considerations:

   • Checkpoint inhibitor usually permanently discontinued (mortality risk too high)
   • Alternative cancer therapies required (chemotherapy, targeted therapy, radiation)

---

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