MYOCARDITIS

MYOCARDITIS 

DEFINITION

Myocarditis = inflammatory disease of the myocardium, diagnosed clinically and/or histologically, with myocardial injury that may produce:

• myocardial necrosis
• ventricular dysfunction
• heart failure
• arrhythmias
• conduction abnormalities
• cardiogenic shock
• sudden cardiac death.

MYOCARDITIS vs MYOPERICARDITIS vs PERIMYOCARDITIS

Practical distinction

Pericarditis + elevated troponin but preserved LV function → myopericarditis

Myocarditis + LV systolic dysfunction → perimyocarditis

The new ESC framework uses “inflammatory myopericardial syndrome (IMPS)” as an umbrella term during initial evaluation because clinical phenotypes frequently overlap. 

ETIOLOGY

Think in infectious, immune-mediated, toxic/drug-related, systemic and genetic categories.

Infectious

A. Viral — most common cause

• Enteroviruses(Coxsackie B)
• Adenovirus
• Parvovirus B19
• HHV-6
• EBV
• CMV
• Influenza
• HIV
• Hepatitis C
• SARS-CoV-2

Important point

• Detection of a virus in blood does not prove that the virus is causing myocardial infection.
• Similarly, routine viral serology is generally not useful for establishing the myocardial etiology.

B. Bacterial

• Borrelia burgdorferi → Lyme carditis
• Corynebacterium diphtheriae → toxin-mediated myocarditis
• Streptococcus
• Staphylococcus
• Mycoplasma
• Chlamydia
• Leptospira
• Salmonella
• Brucella

C. PARASITIC

Trypanosoma cruzi

Chagas disease

Acute myocarditis may progress to chronic cardiomyopathy.

Chronic Chagas:

• dilated cardiomyopathy
• apical aneurysm
• ventricular arrhythmias
• conduction disease
• thromboembolism

Toxoplasma

Important particularly in:

• immunocompromised
• transplant recipients
• advanced HIV

Trichinella

Trichinellosis → eosinophilic myocarditis

D. FUNGAL

Usually immunocompromised patients:

• Candida
• Aspergillus
• Cryptococcus
• Histoplasma

NON-INFECTIOUS / IMMUNE-MEDIATED

Major causes:

• systemic lupus erythematosus
• rheumatoid arthritis
• systemic sclerosis
• inflammatory myopathies
• vasculitis
• sarcoidosis
• giant-cell myocarditis
• eosinophilic myocarditis
• hypereosinophilic syndrome
• inflammatory bowel disease

DRUG-INDUCED MYOCARDITIS

Important causes:

• immune checkpoint inhibitors
• clozapine
• some antibiotics
• sulfonamides
• anticonvulsants
• vaccines — rare association
• cocaine and other cardiotoxic substances

IMMUNE CHECKPOINT INHIBITOR (ICI) MYOCARDITIS

CTLA-4 inhibitors

• ipilimumab

PD-1 inhibitors

• nivolumab
• pembrolizumab
• cemiplimab

PD-L1 inhibitors

• atezolizumab
• durvalumab
• avelumab

ICI myocarditis is uncommon but potentially rapidly fatal.

Particularly important because it may coexist with:“Triple M syndrome”

Myocarditis + Myositis + Myasthenia gravis

This combination can cause:

• myocarditis
• complete heart block
• ventricular arrhythmias
• respiratory muscle weakness
• respiratory failure.

Recent ACC expert discussion emphasizes early recognition and aggressive management in fulminant ICI myocarditis. 

TOXINS

• alcohol
• cocaine
• anthracyclines
• catecholamine excess
• carbon monoxide
• heavy metals

Some toxins produce a myocarditis-like inflammatory phenotype while others primarily cause direct myocardial injury.

GENETIC PREDISPOSITION

Some patients with myocarditis have an underlying genetic susceptibility to myocardial injury/cardiomyopathy.

Genes associated with cardiomyopathy include:

• TTN
• LMNA
• DSP
• FLNC
• DES
• BAG3

The 2024 ACC pathway highlights genetic predisposition and recommends consideration of genetic counseling/testing, particularly because myocarditis may represent an inflammatory trigger acting on an underlying cardiomyopathic substrate. 

HISTOPATHOLOGICAL TYPES

1. Lymphocytic myocarditis

Most common pattern.

Predominantly:lymphocytic infiltration + cardiomyocyte injury

2. Giant-cell myocarditis

Characteristic:

• multinucleated giant cells
• extensive inflammatory infiltrate
• myocardial necrosis

Clinical clue:

Rapidly progressive HF + ventricular arrhythmias/conduction disease ± cardiogenic shock

This is a major biopsy diagnosis because treatment is immunosuppressive.

Giant-cell myocarditis should particularly be considered in rapidly progressive HF/shock that does not respond to usual therapy. 

3. Eosinophilic myocarditis

Predominant:Eosinophilic infiltration

Causes:

• drug hypersensitivity
• hypereosinophilic syndrome
• EGPA
• parasitic infection
• malignancy
• idiopathic disease

Clinical clues:

• eosinophilia
• rash
• fever
• drug exposure
• rapidly progressive HF

Treatment is usually etiology-directed, frequently including corticosteroids.

4. Granulomatous myocarditis

Think:

• cardiac sarcoidosis
• tuberculosis
• fungal infection
• giant-cell processes

CLINICAL PRESENTATIONS

There may be a preceding viral prodrome with fever, malaise, and arthralgias

1. Chest pain (32%)

Looks like:ACS

Features:

• acute chest pain
• ST elevation
• troponin elevation

But coronary angiography may show:Normal coronary arteries

This is often called:MINOCA-like myocarditis

2. Arrhythmic (18%)

• palpitations
• syncope
• presyncope
• ventricular tachycardia
• ventricular fibrillation
• AV block
• sudden cardiac arrest

3. Dysnea(72%)

• Heart failure
• orthopnea
• pulmonary edema
• hypotension
• elevated JVP
• edema
• low cardiac output
• cardiogenic shock.

These three classic presentations are emphasized in the current ACC pathway. 

FULMINANT MYOCARDITIS

Acute myocarditis with:severe hemodynamic compromise/cardiogenic shock

Usually characterized by:

• abrupt presentation
• severe LV dysfunction
• often biventricular dysfunction
• hypotension
• elevated lactate
• end-organ hypoperfusion

May have:

• VT/VF
• high-grade AV block
• cardiac arrest.

Fulminant myocarditis

Often Acute onset + severe LV dysfunction + shock

but if the patient survives the acute phase, ventricular function may recover substantially.

Therefore:Severe acute dysfunction does not necessarily mean irreversible myocardial damage.

CLINICAL EXAMINATION

General

• fever
• tachycardia
• hypotension
• diaphoresis
• malaise

Heart failure

• raised JVP
• S3
• pulmonary crackles
• peripheral edema
• hepatomegaly

Low output

• cold extremities
• altered sensorium
• oliguria
• narrow pulse pressure
• elevated lactate

Pericardial involvement

• pleuritic chest pain
• positional chest pain
• pericardial friction rub
• pericardial effusion

CURRENT ACC STAGING

The 2024 ACC pathway proposes four stages. 

Stage D = ICU-level myocarditis

Examples:

• cardiogenic shock
• sustained VT
• high-grade AV block
• severe hemodynamic compromise.

INVESTIGATIONS 

There are no universally standardized and specific diagnostic criteria for myocarditis, and identifying the exact cause is often difficult.

A specific viral etiology usually cannot be established clinically. Acute and convalescent viral antibody titers are not useful diagnostically because many viruses are common in the general population, antibody levels fluctuate over time, and they do not reliably correlate with the onset of acute myocarditis.

Think:

ECG + troponin + inflammatory markers + echocardiography + CMR ± coronary angiography ± EMB

CBC

May show:

• leukocytosis
• eosinophilia
• anemia
• lymphocytosis

Eosinophilia is a major clue

Think:Eosinophilic myocarditis especially with:new drug,rash,fever,systemic eosinophilic syndrome.

INFLAMMATORY MARKERS

May be elevated:CRP,ESR

But:Normal inflammatory markers do not exclude myocarditis.

CARDIAC TROPONIN

• Usually:↑ troponin,because of cardiomyocyte injury.
• Important:Troponin indicates myocardial injury, NOT the etiology.

Troponin may be elevated in:

• ACS
• myocarditis
• PE
• sepsis
• tachyarrhythmia
• renal failure
• Takotsubo
• severe hypertension.

BNP / NT-proBNP

• Useful when:ventricular dysfunction,Heart Failure
• Higher values generally correlate with worse HF phenotype.

ECG

ECG findings are highly variable and nonspecific.

Possible:

• sinus tachycardia
• ST elevation
• ST depression
• T-wave inversion
• PR depression if pericardial involvement
• low voltage
• QRS widening
• AV block
• bundle branch block
• PVCs
• VT
• VF.

ECG PATTERN

Myopericarditis

• May show:Diffuse ST elevation + PR depression rather than a territorial STEMI pattern.
• But myocarditis can absolutely produce focal ST changes.

ECHOCARDIOGRAPHY

• ECHO FINDINGS Can range from:Normal to Severe global LV dysfunction. to diagnose and quantitate regional and global LV wall motion abnormalities, LV and RV size and function, the presence of pericardial effusion, and valvular regurgitation. RV involvement may be seen in 25% of patients.

MYOCARDITIS vs ACS

This is a major clinical problem.

Both may produce:

• chest pain
• ST changes
• troponin elevation
• regional wall motion abnormality.

Therefore:Do not assume elevated troponin + ST elevation = myocarditis.

If ACS cannot be safely excluded, coronary evaluation is required according to clinical probability.

CARDIAC MRI — KEY INVESTIGATION

CMR is the most important non-invasive test for myocardial tissue characterization.

Current ACC guidance emphasizes CMR for characterization of myocardial edema, hyperemia, necrosis, fibrosis and LV dysfunction. However, cardiac MRI may be normal in patients with milder forms of myocarditis, and it does not distinguish between viral and other etiologies of the disease. It is also more difficult to apply in critically ill patients with cardiogenic shock.

LAKE LOUISE CRITERIA

The updated Lake Louise criteria use CMR evidence of:

T2-based criterion

Evidence of:

myocardial edema

Examples:

• increased T2 signal
• increased T2 mapping values

PLUS

T1-based criterion

Evidence of:

myocardial injury

Examples:

• increased native T1
• increased extracellular volume
• nonischemic LGE.

UPDATED LAKE LOUISE 

T2 = WATER

T1 = INJURY

Therefore:

T2 abnormality → edema

T1 abnormality → myocardial injury

Supportive findings:

• pericardial effusion
• pericardial enhancement
• regional/global LV dysfunction.

LATE GADOLINIUM ENHANCEMENT

• Ischemic injury LGE begins:subendocardial → transmural following a coronary vascular territory.
• Myocarditis-Usually:mid-wall or subepicardial and does not follow a single coronary vascular territory.
• Classic location:inferolateral LV wall especially: subepicardial inferolateral LGE

PROGNOSTIC IMPORTANCE OF LGE

Presence and extent of LGE are clinically important.

Persistent LGE may indicate:

• myocardial fibrosis
• residual inflammation/injury
• increased ventricular arrhythmia risk
• worse outcomes.

The 2024 ACC pathway identifies LGE, biventricular dysfunction and Stage D presentation as adverse prognostic features. 

FDG-PET

• Particularly useful when considering:Cardiac sarcoidosis
• FDG uptake can indicate active inflammation.
• PET may complement CMR rather than replace it.

ENDOMYOCARDIAL BIOPSY — EMB

Not routinely required in every suspected myocarditis.

Why?

Because:

• myocarditis may be patchy
• sampling error
• invasive complications
• many cases can be diagnosed clinically + CMR.

Current ACC guidance specifically limits routine EMB and emphasizes its role when identifying an etiology would change therapy or when mimics must be excluded. 

WHEN TO THINK STRONGLY ABOUT EMB?

Especially:

1. Cardiogenic shock

2. Rapidly progressive HF

3. Severe unexplained LV dysfunction

4. Ventricular arrhythmias

5. High-grade AV block

6. Suspected giant-cell myocarditis

7. Suspected eosinophilic myocarditis

8. Suspected cardiac sarcoidosis

9. Immune checkpoint inhibitor myocarditis

10. Myocarditis where specific therapy depends on histology

These are classic situations in which tissue diagnosis can alter treatment. 

DALLAS CRITERIA

Myocarditis =Inflammatory infiltrate + myocyte necrosis

not attributable to ischemia.

Important limitation:

EMB sensitivity is limited because myocarditis can be patchy.

Thus a negative biopsy does not necessarily exclude myocarditis.

VIRAL PCR ON MYOCARDIAL TISSUE

Viral genome detection ≠ necessarily active viral myocarditis.

Interpretation requires clinical and histopathological context.

Routine broad viral testing is therefore not automatically indicated.

DIFFERENTIAL DIAGNOSIS

• ACS
• myocarditis
• myopericarditis
• Takotsubo
• PE
• coronary vasospasm
• spontaneous coronary artery dissection
• sepsis-related myocardial injury.

MYOCARDITIS vs TAKOTSUBO

MYOCARDITIS vs SEPTIC CARDIOMYOPATHY

Septic cardiomyopathy

Typically:

• systemic sepsis
• global ventricular dysfunction
• reversible
• no primary inflammatory myocardial syndrome necessarily.

Myocarditis

• myocardial inflammation
• troponin often elevated
• CMR abnormalities
• arrhythmias/conduction disease may be prominent.

MANAGEMENT

STABLE MYOCARDITIS WITH PRESERVED LV FUNCTION

Management:

• physical activity restriction
• treat identified cause
• monitor rhythm
• follow troponin/clinical status
• CMR as appropriate
• avoid unnecessary immunosuppression.

HEART FAILURE DUE TO MYOCARDITIS

Treat according to standard HFrEF principles once hemodynamically appropriate:

• ACE inhibitor/ARB/ARNI
• β-blocker
• mineralocorticoid receptor antagonist
• SGLT2 inhibitor
• diuretics for congestion.

But:

Acute decompensated HF

Do not aggressively start/up-titrate all guideline-directed therapy during:

• hypotension
• cardiogenic shock
• severe AKI
• marked bradycardia.

Stabilize first.

NSAIDs AND COLCHICINE

If myocarditis has a pericarditic phenotype with preserved ventricular function:NSAID,colchicine may be used for pericardial inflammation.

But:

Avoid NSAIDs in symptomatic myocarditis with HF/LV dysfunction, because of potential adverse effects and lack of benefit for myocardial inflammation.

The 2024 ACC pathway specifically recommends avoiding NSAIDs/colchicine as myocarditis therapy in symptomatic HF, while allowing their use for pericardial-type chest pain when appropriate. 

IMMUNOSUPPRESSION

Do NOT routinely give steroids to every patient with presumed viral/lymphocytic myocarditis.

Immunosuppression is particularly important in:

• giant-cell myocarditis
• eosinophilic myocarditis
• cardiac sarcoidosis
• immune checkpoint inhibitor myocarditis
• autoimmune/systemic inflammatory disease-associated myocarditis.

This is consistent with current ACC guidance. 

GIANT-CELL MYOCARDITIS

Requires:aggressive immunosuppression

Commonly:

• high-dose corticosteroids
• plus additional immunosuppressive therapy.

Potential agents depending on specialist protocol:

• cyclosporine
• azathioprine
• mycophenolate
• other immunosuppressive strategies.

It often requires prolonged treatment and transplant/advanced-HF evaluation.

EOSINOPHILIC MYOCARDITIS

Treatment:

1. Remove offending agent

if drug-related.

2. Corticosteroids

often highly effective.

3. Treat underlying cause

Examples:

• EGPA → immunosuppression
• parasitic disease → antiparasitic therapy
• HES → hematologic-directed therapy
• PDGFRA-associated disease → imatinib

Eosinophilic myocarditis can rapidly progress to cardiogenic shock. 

CARDIAC SARCOIDOSIS

Treatment generally involves:corticosteroids ± steroid-sparing immunosuppression.

Need to consider:

• PET
• CMR
• arrhythmia monitoring
• ICD depending on risk/indication.

ICI MYOCARDITIS

Stop immune checkpoint inhibitor.

Then:High-dose corticosteroids promptly.

Severe/fulminant cases may require:

• IV methylprednisolone
• additional immunomodulation
• mechanical circulatory support.

Recent ACC expert guidance describes pulse-dose methylprednisolone 500–1000 mg IV daily for 3 days in fulminant ICI myocarditis, alongside stabilization and specialist-directed immunomodulation. 

ACTIVITY RESTRICTION

Exercise can increase:

• catecholamine exposure
• myocardial stress
• arrhythmia risk.

For symptomatic myocarditis, the ACC pathway recommends avoiding strenuous physical activity for approximately 3–6 months, followed by reassessment including appropriate imaging/rhythm/exercise testing before return to strenuous exercise. 

The exact duration should be individualized under contemporary guideline-based follow-up.

FOLLOW-UP

Important because myocarditis can recur or evolve into chronic cardiomyopathy.

Monitor:

• symptoms
• ECG
• troponin when clinically appropriate
• echocardiography
• CMR in selected patients
• rhythm monitoring
• exercise assessment.

ACC suggests repeat echocardiography around 2–4 weeks in Stage C/D myocarditis, with subsequent imaging based on risk. 

PROGNOSIS

Outcome is heterogeneous.

Patients may: Completely recover or Develop persistent LV dysfunction or Develop chronic dilated/inflammatory cardiomyopathy

or

Die from:

• cardiogenic shock
• VT/VF
• complete heart block
• progressive HF.

The ACC consensus notes approximately 50% resolution within 2–4 weeks, about 25% persistent cardiac dysfunction, and 12–25% progression to end-stage HF or death in reported biopsy-proven cohorts; these figures should not be interpreted as universal individual-patient probabilities. 

VACCINE-ASSOCIATED MYOCARDITIS

Most recognized with:

mRNA COVID-19 vaccination

Typical phenotype:

• adolescent/young adult male predominance
• often after second dose
• chest pain
• troponin elevation
• ST/T abnormalities
• generally preserved or mildly reduced LV function.

CMR often demonstrates myocardial edema and nonischemic LGE.

Most cases have favorable short-term recovery, although follow-up is important.