CONTENTS

(1) Causes of HFrEF & investigation

• Causes of HFrEF
• Causes of myocarditis
  • Infection
  • Lyme carditis
  • Lupus & connective tissue dz
  • HLH
  • Sarcoidosis
  • Giant cell myocarditis
  • Eosinophilic acute myocarditis
  • Other drugs/substances
• Evaluating the cause of HFrEF (including myocarditis)
  • History
  • Laboratory studies
  • ECG
  • Echocardiography
  • CMR
  • Ischemic evaluation
  • Endomyocardial biopsy

(2) Myocarditis

• Definitions
• Epidemiology
• Clinical presentation
• Management
• Prognostication & disposition

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causes of HFrEF

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ischemic cardiomyopathy (~66%)

• MINOCA (myocardial infarction with nonobstructive coronary arteries).

HFrEF secondary to another cardiac process

• Hypertension.
• Tachycardia-mediated cardiomyopathy:
  • Atrial arrhythmias.
  • Ventricular arrhythmias.
  • Frequent PVCs (>10-15% of beats).
• Valvular heart disease.
• Secondary to high-output states:
  • Arteriovenous malformation.
  • Arteriovenous fistula.

HFrEF secondary to a specific context

• Takotsubo (stress) cardiomyopathy. 📖
• Peripartum cardiomyopathy. 📖
• Septic cardiomyopathy.

endocrine

• Thyroid disease (hypothyroidism or hyperthyroidism).
• Pheochromocytoma.
• Hyperparathyroidism.
• Acromegaly.

neuromuscular/neurologic

• Friedreich ataxia.
• Duchenne, Becker, Emery-Dreifuss muscular dystrophy.
• Myotonic dystrophy.
• Neurofibromatosis.
• Tuberous sclerosis.

related to nutritional deficiency

• Thiamine (wet beriberi). (32497572)
• Pellagra (niacin; B3).
• Scurvy (vitamin C).
• Keshan disease (selenium).
• Carnitine deficiency.
• Kwashiorkor (protein).

infiltrative & storage diseases, including

• Amyloidosis.
• Gaucher disease.
• Hemochromatosis.
• Glycogen storage disease.

idiopathic (up to 50%)

• Familial dilated cardiomyopathy.

drug or toxin-related

• Alcohol-related cardiomyopathy.
• Sympathomimetics (cocaine, methamphetamine).
• Drugs/substances that cause myocarditis: ⚡️
  • Comment: It's unclear whether all of these medications truly cause myocarditis or merely non-ischemic cardiomyopathy. Lists of cardiotoxic medications in various articles overlap substantially, so they've been consolidated into one section below.  

myocarditis & inflammatory-related dilated cardiomyopathy

• Discussed in the section below 👇
  • Infection
  • Lyme carditis
  • Lupus & connective tissue dz
  • HLH
  • Sarcoidosis
  • Giant cell myocarditis
  • Eosinophilic acute myocarditis
  • Drug or toxin-related

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causes of myocarditis

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infection (~50%)

• Clinical presentation:
  • Prodromal infection may cause flu-like symptoms, respiratory tract symptoms, and/or gastrointestinal symptoms.
• Causative agents:
  • Viruses are most common:
    • Adenoviruses.
    • Enteroviruses (including coxsackieviruses).
    • Parvovirus B19.
    • Influenza.
    • COVID-19.
    • HCV (usually within 1-3 weeks of illness).
    • HIV-1.
    • Dengue virus.
    • Zika virus.
    • EBV, CMV (in the context of immunosuppression).
  • Other infections may also cause myocarditis, including:
    • Toxic shock syndrome & sepsis-related cardiomyopathy.
    • Mycoplasma pneumoniae.
    • Chlamydia psittaci.
    • Coxiella burnetii (Q fever). (38241774)
• Diagnosis:
  • Infection investigation based on epidemiology and clinical clues.
  • Since viral infection may be unrelated to myocarditis, this can remain a diagnosis of exclusion.
• Treatment:
  • Standard treatments are directed at the underlying infection (if possible).
  • Treatment of myocarditis is generally supportive.

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lyme carditis

• Clinical presentation:
  • Often dominated by AV block (high-degree AV block is common).
  • Fulminant myocarditis is extremely rare.
• Diagnosis:
  • Exposure to ticks.
  • Carditis may occur ~1-2 months after infection. (37014337)
  • Serology is positive, but this doesn't prove causality.
  • For patients with a history of tick bites, consider the possibility of coinfection with other tickborne illnesses, which may also cause myocarditis (e.g., babesiosis, ehrlichiosis).
• Treatment:
  • Ceftriaxone 2 grams daily.
  • Alternative: doxycycline 100 mg  BID.
  • Standard supportive care (some patients may require permanent pacemaker insertion).

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lupus (& related connective tissue diseases)

• Causes of myocarditis include:
  • Lupus.
  • MCTD (mixed connective tissue disease).
  • Rheumatoid arthritis.
  • Scleroderma.
  • Inflammatory bowel disease.
  • Dermatomyositis. (33176455)
• Diagnostic clues for lupus myocarditis:
  • ~90% of patients are female.
  • Occurs a median of 2.5 years after lupus diagnosis.
• Treatment of lupus myocarditis may involve:
  • Pulse dose steroid (500-1000 mg/day methylprednisolone x3d, then 0.5-1 mg/kg/d).
  • Additional therapies may include cyclophosphamide or mycophenolate mofetil (500-1500 mg BID). (37014337)

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HLH (hemophagocytic lymphohistiocytosis)

• Further discussion of HLH: 📖

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sarcoidosis

• Clinical presentation:
  • Only 3% of patients with cardiac sarcoidosis present with acute heart failure or shock. (37014337)
  • High-degree AV block is relatively common.
  • Ventricular arrhythmias may occur.
• Further discussion of cardiac sarcoidosis: 📖

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giant cell myocarditis

• Epidemiology:
  • Causes ~10% of fulminant myocarditis (but only ~0.5% of all patients with myocarditis). (33176455)
  • Median age of onset is ~50 years old. (33176455)
• Clinical presentation:
  • Giant cell myocarditis is often severe and progressive, with presentations including:
    • Cardiogenic shock.
    • Ventricular tachycardia.
    • Third-degree AV block.
  • Rapid progression may occur, requiring mechanical support. (37589159)
• Diagnosis:
  • If CMR is performed, widespread late gadolinium enhancement may affect all myocardial layers. (37589159)
  • An endomyocardial biopsy is generally required. Because involvement is diffuse, myocardial biopsy has a high yield (~85%). (37405349). Pathological findings may overlap somewhat with sarcoidosis.
• Treatment:
  • Aggressive immunosuppression may include:
    • Methylprednisolone pulse (1,000 mg/day x3d), then maintenance at 1 mg/kg/day for months with a subsequent slow taper.
    • Calcineurin inhibitor (e.g., tacrolimus or oral cyclosporine twice daily initially targeting trough levels 150-250 ng/ml).
    • Anti-thymocyte globulin (ATG) or IV alemtuzumab (anti-CD52 antibody). (37014337)
  • Inotropes and mechanical support may be needed.
  • ICD placement may be wise (even if the ejection fraction recovers). (33176455)
• Prognosis:
  • The prognosis is generally poor.
  • Traditional statistics quote an ~85% risk of death or cardiac transplantation at three years, but may be improved with aggressive immunosuppression. (34507935, 36260793)

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eosinophilic acute myocarditis

• Clinical presentation may include:
  • Valvular involvement.
  • Endomyocardial thrombus formation.
• Diagnosis:
  • 80% have peripheral eosinophilia. (37014337)
  • Echocardiography and/or CMR may show endomyocardial involvement. (37589159) Unlike most forms of myocarditis, eosinophilic myocarditis is usually associated with subendocardial late gadolinium enhancement. (33176455)
• Causes:
  • Medication-induced (including clozapine and DRESS syndrome 📖).
  • EGPA (eosinophilic granulomatosis with polyangiitis).
  • Hypereosinophilic syndromes.
  • Parasitic infection (e.g., Toxocara canis transmitted by raw meat, trichinosis, toxoplasmosis). (33176455)
  • (Further discussion of eosinophilia with additional etiologies: 📖)
• Treatment:
  • Depends on the specific etiological cause of eosinophilic myocarditis.

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other drug or substance-related myocarditis

• Drug-related hypersensitivity: (Usually occurs within eight weeks of drug initiation. Other features may include rash, fever, and liver function test abnormalities.)(Mayo 5e)
  • Antibiotics: Penicillin, ampicillin, cephalosporins, isoniazid, tetracyclines, sulfonamides.
  • Clozapine (~3% of patients, often within about two weeks of initiation). (37014337; 37589159)
  • Colchicine.
  • Diuretics: Acetazolamide, furosemide, thiazide diuretics, spironolactone.
  • Indomethacin.
  • Lidocaine.
  • Phenytoin, carbamazepine.
  • Sulfonylureas.
  • Tricyclic antidepressants.
• Non-cancer medications with direct cardiotoxicity:
  • Anabolic steroids.
  • Catecholamines (including amphetamine and cocaine).
  • Interleukin 2.
  • Lithium. (38536007)
• Cancer therapies:
  • Anthracyclines and mitoxantrone.
  • Alkylating agents: cyclophosphamide, ifosfamide.
  • Bevacizumab.
  • Checkpoint inhibitors (see: cardio-oncology chapter 📖)
  • Clofarabine.
  • Docetaxel.
  • Fluorouracil.
  • Proteasome inhibitors: bortezomib, carfilzomib.
  • Radiotherapy.
  • Trastuzumab.
  • Tyrosine kinase inhibitors: dasatinib, lapatinib, imatinib, sunitinib.
• DRESS syndrome: 📖
• Allergens: Tetanus toxoid, vaccines, serum sickness.
• Heavy metal toxicity (copper, iron, lead, arsenic).

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evaluating the cause of HFrEF (including myocarditis)

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history

• Recent infection.
• Recent travel.
• Rheumatologic disorder.
• Asthma.
• Substance use (alcohol, sympathomimetics).
• Medication exposure.
• Vaccine exposure.
• Raw meat exposure (may cause Toxocara canis-related eosinophilic myocarditis).
• Family history of myocarditis, cardiomyopathy, sudden death, or autoimmune disease.

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laboratory studies to investigate HFrEF (or suspected myocarditis)

• Basic labs:
  • Complete electrolytes (including Ca/Mg/Phos).
  • CBC with differential cell count (to evaluate for eosinophilia).
  • Liver function tests.
  • Urinalysis, including sediment analysis (nephritis may raise a suspicion for lupus).
  • Troponin.
    • In myocarditis, wall motion abnormalities may be disproportionately greater than expected based on the degree of troponin elevation.
    • Higher troponin levels may correlate with more acute, fulminant myocarditis. 
    • Lower troponin levels may paradoxically correlate with worse long-term outcomes (since this implies a chronic smoldering process with less reversibility).  (Griffin 2022)
  • Creatinine kinase (marked elevation may suggest a global myopathic process).
  • Lactate (if concern for occult shock).
• Infection workup:
  • Nasopharyngeal PCR for viruses (COVID, influenza, community-acquired respiratory viruses).
  • HIV screen.
  • HCV screen in high-risk populations. (38536007)
  • Lyme serology.
  • Consider evaluation for EBV and CMV (if suggestive history or immunosuppression).
• Inflammatory markers:
  • CRP (C-reactive protein) is elevated in >80% of patients with acute myocarditis. (34507935)
  • Ferritin level.
• ANA (anti-nuclear antigen).
• TSH (thyroid stimulating hormone; evaluation for thyroid storm).
• May also consider:
  • Urine toxicology screen (evaluation for sympathomimetic exposure).
  • If suspect ANCA vasculitis: ANCA, anti-MPO, anti-PR3.
  • Plasma and 24-hour urine metanephrines (if history suggests pheochromocytoma, which may cause catecholamine-mediated myocarditis). (34507935)
  • Thiamine level.
  • Serum protein electrophoresis if concern for amyloidosis.

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ECG

ECG findings in myocarditis

• ECG for the diagnosis of myocarditis is discussed here: 📖
• ECG-based prognosis is discussed below: ⚡️

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echocardiography

echocardiography in myocarditis

• Wall motion abnormalities may be seen.
  • These may clearly deviate from a coronary artery distribution.
  • Wall motion abnormalities often involve the inferior and especially lateral walls. (37014337)
• Increased myocardial wall thickness and abnormal echogenicity may be noted due to edema.
  • Unlike chronic forms of dilated cardiomyopathy, the left ventricular cavity is not dilated in acute myocarditis, and the walls are thickened (rather than thinned out). This may generate a relatively small left ventricular cavity, leading to a relatively low cardiac output (because the stroke volume is low).
• Pericardial effusion may occur (if there is perimyocarditis).

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CMR

CMR in ischemic cardiomyopathy

• T2 enhancement is generally not seen (this would indicate acute infarction).
• LGE has a characteristic distribution:
  • Begins in the subendocardium, with an extension to transmural.
  • It is located in a coronary artery distribution.

CMR in myocarditis: indications & performance

• Indications for CMR in myocarditis:
  • Evaluation for possible myocarditis (e.g., patients with chest pain, elevated troponin, and normal coronary anatomy). (33176455)
  • CMR should ideally be performed in all patients with known acute myocarditis who are stable enough to tolerate it. (32497572; 37589159) CMR contrast enhancement may help predict the yield of endomyocardial biopsy and guide the optimal location of a myocardial biopsy. (Griffin 2022)
• Performance of CMR in myocarditis diagnosis:
  • CMR has reduced accuracy within the first few days of illness. (34507935) Sensitivity is highest if performed 2-3 weeks after initial presentation. (36260793)
  • CMR is less sensitive for patients with an arrhythmic presentation. (32497572)
  • CMR has impaired performance in the presence of myositis (since skeletal muscle is used as a reference standard). (37589159)

CMR in myocarditis: findings

• Tissue edema (hyperintensity on T2)
  • Patchy areas of edema are usually seen with matching areas of LGE (late gadolinium enhancement).
  • Edema is located in a a non-coronary distribution. The basal inferolateral wall is often involved, but edema may also be distributed globally. (38536007)
  • Edema often extends from the sub-epicardium downwards into the myocardium (whereas myocardial infarction typically extends from the endocardium outwards). (32497572)
  • Edema usually declines four weeks after onset. (33176455)
• LGE (late gadolinium enhancement):
  • Like tissue edema, LGE is typically subepicardial and mid-myocardial, sparing the endocardium. (Gaggin 2021)
  • LGE indicates an increased risk of major adverse events, especially in the anteroseptal region. (Gaggin 2021, 38536007)
  • LGE usually persists, although it may decrease in extent over time. (33176455) Persistent LGE without tissue edema implies the presence of scar, so this is a poor prognostic sign (as opposed to the combination of edema plus LGE, which suggests an active and potentially reversible process).

CMR in sarcoidosis

• Early: may see patchy high signal intensity on T2-weighted black blood images due to localized inflammation, with focal patchy areas of hyperenhancement.
• Involvement of the basal anteroseptal wall is characteristic. (Griffin 2022)

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ischemic evaluation

• Coronary disease is common, so it should always be carefully considered and excluded.
• Evidence that may help risk-stratify the likelihood of coronary artery disease:
  • ECG findings.
  • Troponin levels (in myocarditis or Taktosubo cardiomyopathy, troponin levels may be lower and less dynamic compared to patients with myocardial infarction and a similar degree of myocardial dysfunction).
  • Coronary calcification (e.g., on CT scan).
• Options to evaluate for coronary artery disease:
  • Invasive cardiac catheterization (preferred for patients at moderate/high risk of coronary artery disease).
  • CT coronary angiography.
  • CMR (if CMR is clearly myocarditis and inconsistent with ischemia, further ischemic evaluation is unnecessary). (38763214)

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endomyocardial biopsy

in myocarditis, possible indications for biopsy include 

• Suspicion for giant cell myocarditis or eosinophilic myocarditis.
• Fulminant myocarditis.
• Failure to respond to usual care within 1-2 weeks.
• Persistent release of troponin.

histological classifications of myocarditis

• Lymphocytic myocarditis (~75%) is the most common histological form. Finding this is relatively nonspecific regarding the precise etiology of myocarditis.
• Eosinophilic myocarditis: ⚡️
• Giant cell myocarditis: ⚡️
• Cardiac sarcoidosis (~3%): ⚡️

complications of endomyocardial biopsy

• Supraventricular arrhythmias.
• Pericardial effusion/tamponade due to perforation (right-sided biopsy).
• Stroke or systemic embolism (left-sided biopsy).
• Transient heart block. (37014337)

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definitions

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chronicity-based classification

• Acute myocarditis: <1 month between symptom onset and diagnosis.
  • Fulminant myocarditis: Acute myocarditis requiring therapy with inotropes and/or mechanical support. This is more common among giant cell myocarditis or eosinophilic myocarditis. (31778001)
• Subacute myocarditis: >1-3 months between symptom onset and diagnosis.
• Chronic inflammatory cardiomyopathy: symptoms persist for >1 month (this overlaps with subacute myocarditis). (34507935)

complicated vs. uncomplicated acute myocarditis is discussed in the prognostication section below: ⚡️

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epidemiology of myocarditis

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• Acute myocarditis is a heterogeneous group of conditions, with epidemiology varying between different etiologies.
• Patients are often relatively young (e.g., <50 years old). (34507935) Myocarditis may account for up to 7% of young people with sudden death. (38241774)
• Men account for ~70% of patients, which is felt to reflect that testosterone promotes inflammation. (33176455)

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clinical presentation of myocarditis

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there is often a prodromal viral-type illness (~50%)

• Flu-like illness.
• Gastrointestinal disorder.
• Upper respiratory tract infection.
• Rash may occur.

symptoms of myocarditis may include

• [1] Chest pain (~90%).
  • Pain may resemble pericarditis among patients with myopericarditis (which may be marked by positional and pleuritic chest pain).
  • Pan can mimic anginal chest pain.
  • Pain tends to be associated with ST-T changes. (38763214)
• [2] Dyspnea (~30%).
  • This may reflect congestive heart failure.
  • Cardiogenic shock can also occur.
• [3] Syncope (6%), palpitations, or electrically diagnosed arrhythmia. (33176455)
  • Supraventricular tachycardia.
  • Ventricular tachycardia:
    • Polymorphic ventricular tachycardia occurs in active myocarditis.
    • Regular, monomorphic ventricular tachycardia occurs in chronic myocarditis. (36260793) 
  • Bradycardia is uncommon but can occur with sarcoidosis or systemic autoimmune disease. (38241774)
  • Sync0pe presentation correlates with high risk of death or transplantation. (Mayo 5e)
• Fever (~65%).

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management of myocarditis

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indication for immunosuppression

• Potential indications to consider immunosuppression:
  • Myocarditis associated with systemic autoimmune disorders.
  • Giant cell myocarditis.
  • Cardiac sarcoidosis.
  • Eosinophilic myocarditis.
  • Multisystem inflammatory syndrome due to COVID-19.
  • Checkpoint inhibitor-associated myocarditis.
  • Severe illness severity (controversial, largely unknown).
• Further treatments directed at the underlying etiology are discussed in the sections above:
  • Lyme carditis
  • Lupus & connective tissue dz
  • HLH
  • Sarcoidosis
  • Giant cell myocarditis
  • Eosinophilic acute myocarditis

reduced LVEF with stable hemodynamics

• Treatment is similar to patients with HFrEF, e.g.:
  • ACE inhibitor or ARB; angiotensin receptor-neprilysin inhibitors.
  • Beta-blockers.
  • Mineralocorticoid receptor antagonists.
  • Sodium-glucose cotransporter 2 inhibitors.

reduced LVEF with unstable hemodynamics

• Inotropic support.
• Mechanical support (e.g., IABP, impella, ECMO).
  • Ideally, it is a bridge to recovery.
  • If there is no recovery, it may bridge to cardiac transplantation or durable LVAD.
• Further discussion of the management of heart failure & cardiogenic shock: 📖

anticoagulation

• Usually recommended for patients with apical aneurysm to reduce the risk of left ventricular thrombus. (Griffin 2022)

electrophysiological interventions

• Sarcoidosis and giant cell myocarditis are the most likely diagnoses in patients with myocarditis and ventricular arrhythmias. (38763214)
• Transcatheter ablation may be used for arrhythmia management in some patients. (38536007) However, arrhythmias often improve with a resolution of inflammation, so invasive treatments should usually be avoided. (38763214)
• Pacemaker and/or ICD insertion depends on the underlying etiology and anticipated prognosis.

patients with pericardial involvement (perimyocarditis)

• Colchicine is advisable.
• NSAIDs aren't recommended in myocarditis (due to ineffectiveness and potential exacerbation of myocarditis in animal models). (34507935)

parameters to follow over time as part of a treatment regime

• Troponin:
  • A steep decline in troponin is a favorable prognostic feature.
  • Recurrent or persistently elevated troponin suggests ongoing inflammation (as may occur due to a systemic inflammatory disorder or cardiac sarcoidosis). (32497572)
• Inflammatory markers.
• Serial echocardiography:
  • Evaluation of left ventricular function.
  • Evaluation for the development of pericardial effusion/tamponade.

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prognostication & disposition

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complicated vs. uncomplicated acute myocarditis

• Complicated myocarditis is defined as one or more of the following:
  • [1] LVEF <50%.
  • [2] Sustained ventricular arrhythmias.
  • [3] Hemodynamic instability (heart failure or cardiogenic shock).
  • [4] High-degree AV block.
• Prognosis:
  • Complicated myocarditis carries a 10% risk of mortality or cardiac transplant after one month. (38241774)
  • Uncomplicated acute myocarditis has a reasonably favorable prognosis. (32497572)

ECG features that are poor prognostic indicators

• Interval prolongation:
  • Second or third-degree AV block.
  • QRS >120 ms.
  • Prolonged QT interval.
• Ventricular arrhythmias.
• Evidence of myocardial functional loss:
  • Low voltage (may correlate with diffuse myocardial edema in fulminant myocarditis). (Mayo 5e)
  • Q-waves.

other poor prognostic features

• Very high troponin level is a marker of high risk. (32497572)
• Right ventricular dysfunction. (Mayo 5e)

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questions & discussion

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