Myocarditis medical therapy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Varun Kumar, M.B.B.S.; Maliha Shakil, M.D. [2] Homa Najafi, M.D.[3]

Symptomatic treatment is the mainstay of therapy for patients with viral myocarditis. Supportive therapy includes diuretics and inotropes for left ventricular failure. ACE inhibitor therapy may aid in left ventricular remodeling. Among patients with fulminant myocarditis, placement of either an intra-aortic balloon pump or a left ventricular assist device may be necessary as bridge to recovery. Administration of antimicrobial therapy is recommended for bacterial myocarditis. Immunosuppressive therapy may be effective in the management of giant cell myocarditis, autoimmune myocarditis, and eosinophilic myocarditis. In patients with arrythmias, treatment should be initiated only if arrhythmias are symptomatic or sustained. Myocarditis patients presenting with conduction abnormalities, particularly Mobitz type II and complete heart block require temporary pacemaker usually during the acute phase.

• Pharmacological treatment of myocarditis is initiated once the diagnosis is established and, in some cases with clinical instability, when myocarditis is highly suspected.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine are used for pericarditis type chest pain but should be avoided in cases of symptomatic heart failure.^[1]
• Immunosuppressive therapy is generally used in cases of eosinophilic myocarditis, giant cell myocarditis, cardiac sarcoidosis, and immune checkpoint inhibitor-associated myocarditis. When endomyocardial biopsy identifies one of these specific etiologies, etiology-directed therapy should be initiated promptly.^[2][3][4][5]
• Viral PCR on endomyocardial biopsy tissue should be performed to exclude active infection prior to initiation of immunosuppressive therapy. Experts from certain centers advise treating chronic lymphocytic myocarditis with negative viral PCR with immunosuppressive therapy.^[3][2][4]
• Intravenous immunoglobulin (IVIG) can be considered in the setting of inflammatory, antibody-mediated, or autoimmune disorders.^[6]

• The mainstay of therapy for viral myocarditis is supportive care and standard management of CHF.^{[7][8][9][10][11][12][11][13] [14][15][16][17][18][19][20][21][22][23][24]}
• The Heart Failure Society of America recommends against the routine use of immunosuppressive agents in treatment of myocarditis.

• Animal studies have demonstrated better outcomes in viral myocarditis with the use of antiviral agents and interferon early in the course of infection prior to inoculation. The use of antiviral therapy may be limited since patients with viral myocarditis are usually not seen in the early stages. However, it may be used in acute, fulminant myocarditis and in institutional outbreaks. In a series, 6 months of beta interferon in patients with myocarditis secondary to enterovirus or adenovirus infection resulted in the elimination of viral genomes in all patients and improvement of LV function in 68% of the patients.

• Immunotherapy was thought to be a treatment option for myocarditis as they suppress the activity of immunologic agents mediating myocardial inflammation. There is no significant change in mortality rate with immunotherapy. However, improvement in LV function is seen in patients with chronic inflammatory dilated cardiomyopathy.
• The benefits of immunosuppression in lymphocytic myocarditis assessed in large prospective randomized clinical trials remain an unanswered question and a priority for future research.

• Intravenous immunoglobulin (IVIG) is known to have both antiviral and immunologic properties. Therefore, it can be used in both viral and autoimmune types of myocarditis.
• Temporary pacemaker insertion is indicated in patients with symptomatic bradycardia and/or heart block during the acute phase of myocarditis.
• ICD implantation is not indicated during the acute phase of myocarditis.
• Antiarrhythmic therapy can be useful in patients with symptomatic NSVT or sustained VT during the acute phase of myocarditis.

• Giant cell myocarditis requires a higher level of immunosuppression than IV steroids alone, typically including a calcineurin inhibitor (cyclosporine or tacrolimus)
• Giant cell myocarditis is a rare form of myocarditis and is generally associated with a poor prognosis. In a non-randomized series, 22 patients with giant cell myocarditis who were treated with corticosteroids and cyclosporine/azathioprine, survived for an average of 12.3 months. In contrast, those patients who were not treated with immunosuppressants survived for an average of 3 months. Use of immunosuppressive therapy was further strengthened by a prospective, multicenter observational study which reported an improved survival of 6 years among patients receiving high dose steroids and cyclosporine with or without muromonab-CD3. Of the 11 patients studied, two patients underwent cardiac transplantation early in the course of the study and one patient died. The study also reported that withdrawal of immunosuppression was associated with a recurrence of giant cell myocarditis in some patients which in some cases was fatal. Immunosuppressive therapy directed at T-cells may be beneficial as T-cells mediate myocardial inflammation.^[25][26][27]

• Cardiac transplantation is sometimes required to treat refractory giant cell myocarditis. However, the condition can recur in post-transplant patients. Recurrence of biopsy proven giant cell myocarditis between 3 weeks to 9 years was observed in 9 of 34 cardiac transplant patients.

• Eosinophilic myocarditis can occur secondary to hypersensitivity to drugs, parasitic infestation, or hypereosinophilic syndrome. The eosinophils which infiltrate the myocardium, degenerate leading to extracellular release of eosinophil granules which can contribute to death of myocytes. Usage of immunosuppressants such as high dose steroids (after excluding infections) and removal of offending drug (in drug induced hypersensitivity) is known to be beneficial in treatment of eosinophilic myocarditis. Immunosuppressive therapy may be tapered gradually after one year if normal cardiac function and cardiac enzymes levels are restored.^[28][29]

• Myocarditis can develop in autoimmune diseases such as celiac disease and sarcoidosis. Treatment with gluten-free diet and immunosuppressants in celiac disease improves cardiac function. Corticosteroids are found to be beneficial in patients with sarcoidosis related myocarditis, particularly during initial stages of the disease before development of extensive fibrosis of myocardium.^[30][31]

• As heart failure in patients with myocarditis has poor prognosis, it is important to prevent progression or worsening of cardiac dysfunction. These patients should be treated with low sodium intake, diuretics and ACE inhibitors. Few animal studies report that mortality rate is high with digoxin in comparison to beta blocker in viral myocarditis. Studies have also demonstrated that usage of carvedilol during recovery phase decreases expression of several histochemicals and subsequently myocardial inflammation and there by improving survival. The beta-blockers should however be avoided in the acutely decompensating phase of illness. If heart failure or cardiogenic shock does not respond to medical therapy, circulatory support with an intraaortic balloon pump should be considered which could be used in fulminant myocarditis as a bridge to spontaneous recovery. Implantation of ICD in severe heart failure should be deferred for several months to allow sufficient time for recovery of ventricular function. Following the initial circulatory stabilization, further treatment of cardiac dysfunction should follow current ACC/AHA recommendations. Anticoagulation may be considered in patients with severe/chronic heart failure as they are at risk for developing thromboembolic complications.^{[32][33][34][35][36][37][38]}

• Heart failure complicating myocarditis should be managed in accordance with guideline-directed medical therapy (GDMT). The 2024 ACC Expert Consensus Decision Pathway explicitly endorses the evidence-based approach to heart failure management recommended in the 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure for all patients with myocarditis-associated cardiac dysfunction.^[6]
• Current GDMT for heart failure with reduced ejection fraction (HFrEF, defined as LVEF ≤40%) comprises four evidence-based medication classes.^[39]
  • Angiotensin receptor-neprilysin inhibitors (ARNi): Sacubitril-valsartan is the preferred renin-angiotensin system agent in eligible patients with HFrEF (Class I, Level of Evidence A). Where ARNi is not feasible, an ACE inhibitor or angiotensin receptor blocker (ARB) remains appropriate.^[39]
  • Beta-blockers: Carvedilol, metoprolol succinate, or bisoprolol are recommended in stable patients with HFrEF. Beta-blockers should be used with caution or avoided during the acutely decompensated phase of myocarditis.^[39]
  • Mineralocorticoid receptor antagonists (MRA): Spironolactone or eplerenone are recommended in patients with HFrEF without contraindications.^[39]
  • Sodium-glucose cotransporter-2 inhibitors (SGLT2i): Dapagliflozin or empagliflozin are now a Class I, Level of Evidence A recommendation for HFrEF, providing reduction in cardiovascular mortality and HF hospitalization independent of diabetes status. SGLT2 inhibitors also carry a Class IIa recommendation in heart failure with mildly reduced ejection fraction ( LVEF 41–49%) and a Class IIa recommendation in heart failure with preserved ejection fraction (HFpEF, LVEF ≥50%).^[39]
  • Diuretics remain important for relief of congestive symptoms and volume overload but do not independently reduce mortality.^[39]
  • Digoxin should be avoided in viral myocarditis, as animal studies have demonstrated a higher mortality rate with digoxin compared to beta-blocker therapy.^[39]
  • Anticoagulation may be considered in patients with severe or chronic heart failure at risk for thromboembolic complications.^[39]
  • Simultaneous initiation or early combination of all four GDMT pillars may be considered rather than strict sequential titration, based on individual clinical status.^[39]
  • For more information on heart failure treatment, click here.

• Arrhythmias or conduction abnormalities can occur in patients with myocarditis. Treatment should be initiated only if arrhythmias are symptomatic or sustained. Caution should be observed while using antiarrhythmics as majority of these agents have negative inotropic property which may worsen heart failure. Regular monitoring with ECG is important as it enables early detection and treatment of asymptomatic yet life threatening arrhythmias.
• Supraventricular tachycardia (SVT) can aggravate heart failure. Symptomatic and sustained SVT should be immediately converted electrically. While, patients with recurrent sustained SVT should be treated with antiarrhythmics and rate controlling agents. Implantation of ICD should be considered in patients with recurrent ventricular arrhythmia refractory to medical therapy. Myocarditis patients presenting with conduction abnormalities, particularly Mobitz type II and complete heart block require temporary pacemaker usually during the acute phase. Implantation of permanent pacemaker or ICD may be necessary in few patients.^[40]

Patients with Stage D myocarditis and cardiogenic shock require prompt consideration oftemporary circulatory support. The need for temporary circulatory support should be consideredif not previously implemented.

• Whether unloading of the left ventricle for those on extracorporeal membrane oxygenation (ECMO) improves outcomes is an important unanswered research question.^[41][42]
• A small minority of patients with myocarditis will not recover and will require transition to a durable LVAD or heart transplantation.^[6]

• Restriction of strenuous physical activity is a central component of myocarditis management. All patients with Stage C or Stage D myocarditis should be educated to refrain from strenuous physical activity and competitive sports until formally cleared to return to such activities.^[6]
• In patients with Stage C or Stage D myocarditis, strenuous physical activity and competitive sports should be avoided for 3–6 months following the initial diagnosis.^[6]
• A reassessment for return to strenuous physical activity, including competitive sports, is performed at 3–6 months after initial diagnosis. In some athletes, these assessments can be made as early as 3 months after the initial episode of myocarditis for consideration of return to competitive sports.^[6]
• Safety for return to strenuous physical activity is guided by the following assessments, typically at the 6-month follow-up visit:^[43][44][45]

1. Follow-up CMR with T1 and T2 parametric mapping, or echocardiography, to confirm resolution of myocardial edema and normalization of left ventricular ejection fraction.
2. 24-hour ambulatory ECG monitoring (Holter) to exclude significant arrhythmia burden.
3. Exercise stress testing to assess functional capacity and exclude exercise-induced arrhythmia.

• Required care does not end even if symptoms resolve after 2–3 weeks. Patients with myocarditis require longitudinal follow-up with repeat assessment of circulating biomarker levels, echocardiography, and usually a follow-up CMR.^[6]

1. At 2–4 weeks: A repeat echocardiogram with an office visit is recommended for all Stage C and Stage D patients. This allows detection of new or progressive deterioration of left ventricular function suggestive of a diagnosis of giant cell myocarditis.^[6]
2. At 6 months: A second follow-up imaging study is recommended, stratified by risk:^[6]
   1. For low-risk Stage C patients (normal LVEF, no electrical or hemodynamic instability): repeat echocardiogram.
   2. For higher-risk Stage C or Stage D patients: repeat CMR with T1 and T2 parametric mapping.
3. Serial biomarker monitoring: Serial measurement of high-sensitivity cardiac troponin and natriuretic peptides may be used to assess for evidence of subclinical deterioration between scheduled imaging studies.^[46]
4. ICD implantation in patients with severe heart failure should continue to be deferred for several months to allow sufficient time for recovery of ventricular function, consistent with existing recommendations.

Stage A: At-Risk for Myocarditis

• Monitor for progression to higher stages of myocarditis
• Remove offending agent and avoid reexposure when feasible
• Counsel patient of risk

Stage B Myocarditis

• Hospitalization depending upon clinical context and severity of myocardial involvement
• Reassess for presence of symptoms
• Obtain ECG if not done before
• Remove offending agent and avoid reexposure when feasible
• Treat by etiology
• Repeat imaging (echocardiogram and/or CMR)
• Outpatient genetic counseling and testing

Stage C Myocarditis

• Hospitalization if not low-risk presentation
• Triage for referral to advanced heart failure center with a myocarditis team
• Endomyocardial biopsy in select patients
• Pharmacological treatment as appropriate: ** Immunosuppression directed at etiology ** Guideline-directed medical therapy (GDMT) for heart failure
• Restrict strenuous physical activity for 3–6 months (avoid excessive sedentary behavior)
• Repeat imaging (echocardiogram and/or CMR) and biomarkers (e.g., cardiac troponin)
• Outpatient genetic counseling and testing

Stage D Myocarditis

• ICU admission
• Refer to an advanced heart failure center with a myocarditis team
• Treat arrhythmia
• Hemodynamic support including temporary circulatory support as needed
• Endomyocardial biopsy
• Pharmacological treatment: ** Immunosuppression directed at etiology ** GDMT for heart failure and shock
• Consider durable LVAD or heart transplant if no recovery
• Restrict strenuous physical activity for 3–6 months (avoid excessive sedentary behavior)
• Repeat imaging (echocardiogram and/or CMR) and biomarkers (e.g., cardiac troponin)
• Outpatient genetic counseling and testing

Class I

1. Temporary pacemaker insertion is indicated in patients with symptomatic bradycardia and/or heart block during the acute phase of myocarditis. (Level of Evidence: C)

2. Acute aortic regurgitation associated with VT should be treated surgically unless otherwise contraindicated.(Level of Evidence: C)

3. Acute endocarditis complicated by aortic or annular abscess and AV block should be treated surgically unless otherwise contraindicated. (Level of Evidence: C)

Class III

1.ICD implantation is not indicated during the acute phase of myocarditis. (Level of Evidence: C)

Class IIa

1. ICD implantation can be beneficial in patients with life-threatening ventricular arrhythmias who are not in the acute phase of myocarditis, as indicated in the ACC/AHA/NASPE 2002 guideline update for implantation of cardiac pacemakers and antiarrhythmic devices who are receiving chronic optimal medical therapy, and who have reasonable expectation of survival with a good functional status for more than 1 year. (Level of Evidence: C)[48]

2. Antiarrhythmic therapy can be useful in patients with symptomatic NSVT or sustained VT during the acute phase of myocarditis. (Level of Evidence: C)

Class I

1. It is recommended that patients with a life-threatening presentation of sustained ventricular tachyarrhythmias in the context of clinically suspected myocarditis are referred to specialized centers with the ability to perform hemodynamic monitoring, cardiac catheterization and endomyocardial biopsy and to use mechanical cardio–pulmonary assist devices and specialized arrhythmia therapies. (Level of Evidence: C)[50][51][52][53]

2. Temporary pacemaker insertion is recommended in patients with bradycardia and/or heart block triggering VA during the acute phase of myocarditis/pancarditis.(Level of Evidence: C)[50][54]

Class IIa

1.Anti-arrhythmic therapy should be considered in patients with symptomatic non-sustained or sustained VT during the acute phase of myocarditis.(Level of Evidence: C)[50]

2. The implant of an ICD or pacemaker in patients with inflammatory heart diseases should be considered after resolution of the acute episode. (Level of Evidence: C)[50][55]

3. In patients with hemodynamically compromising sustained VT occurring after the resolution of acute episodes, an ICD implantation should be considered if the patient is expected to survive >1 year with good functional status. (Level of Evidence: C)

4. A wearable defibrillator should be considered for bridging until full recovery or ICD implantation in patients after inflammatory heart diseases with residual severe LV dysfunction and/or ventricular electrical instability. (Level of Evidence: C)[56][57]

Class IIb

1. ICD implantation may be considered earlier in patients with giant cell myocarditis or sarcoidosis who had hemodynamically compromising sustained VA or aborted cardiac arrest, due to adverse prognosis of these conditions, if survival >1 year with good functional status can be expected. (Level of Evidence: C)[58]

2. Demonstration of persistent myocardial inflammatory infiltrates by immunohistological evidence and/or abnormal localized fibrosis by CMR after acute myocarditis may be considered as an additional indicator of increased risk of SCD in inflammatory heart disease. (Level of Evidence: C)[59]

Class IIa

1. NSAIDs (together with proton pump inhibition) should be considered in patients with associated symptoms of pericarditis to reduce symptoms.(Level of Evidence: C)

2.Colchicine should be considered in patients with myopericarditis to reduce recurrences. (Level of Evidence: B)

Class I

1.Adherence to the ESC Heart Failure guidelines is recommended in cases of myocarditis with LV systolic dysfunction and/or HF to reduce symptoms and to improve LV function. (Level of Evidence: C)

Class IIa

2.HF therapy should be considered in patients with myocarditis and LV systolic dysfunction for at least 6 months upon complete LV functional recovery to stabilize LV function.(Level of Evidence: C)

Class IIa

1.β-Blockers, with a continuation for at least 6 months, should be considered in patients with acute myocarditis, especially those with troponin elevation, to control symptoms and prevent arrhythmias.(Level of Evidence: C)

2.Anti-arrhythmic treatment should be considered in post-myocarditis patients with recurrent, symptomatic VT to reduce arrhythmic burden.(Level of Evidence: B)

Class IIa

1.Corticosteroids should be considered in patients with fulminant, non-infectious forms of myocarditis to stabilize the patients. (Level of Evidence: C)

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