Acute myocarditis is a rare condition characterized by cardiac inflammation which may result in impaired cardiac function, arrhythmias and conduction disturbances. The presentation may be fulminant, requiring pharmacologic or mechanical circulatory support or can result in sudden cardiac death; milder cases can be self‐limiting but may progress to dilated cardiomyopathy with eventual chronic heart failure (HF).

Although the aetiology of acute myocarditis is varied, the most common cause is viral infection of the myocardium. ¹ Common viruses associated with myocarditis include adenovirus, enterovirus, parvovirus B19, herpes virus, Epstein–Barr virus and cytomegalovirus. ¹ Other viruses that uncommonly cause myocarditis include hepatitis C, ² the human immunodeficiency virus, ¹ and the SARS‐CoV‐2 coronavirus. ³

In addition to viruses, myocarditis can be triggered by other infectious processes such as Chagas disease, Lyme disease and even diphtheria. ¹ Myocarditis can also be precipitated by a large number of chemical entities; examples include the more recently introduced checkpoint inhibitors. ⁴ Some antipsychotic agents such as clozapine can also induce inflammation in the myocardium. ¹ Finally, myocarditis has also been reported in association with a number of clinical syndromes, including reactions to certain drugs, such as penicillin, and secondary to autoimmune diseases such as lupus and Sjogren's disease.

The exact pathophysiology of myocarditis is not completely understood. In viral infection‐mediated myocarditis, viral proliferation in myocytes can cause direct tissue injury. However, most tissue damage in myocarditis results from the interaction of the viral trigger with the immune system. The immune response is activated to eliminate virus‐infected cells to control the infection. Further, intracellular components released from necrotic myocytes may trigger an autoimmune response by molecular mimicry with viral antigens. ⁵ It is the autoimmune response that results in continued cell necrosis, inflammation, development of fibrosis and further impairment in cardiac function and is believed to lead to the development of chronic dilated cardiomyopathy. It is acute idiopathic or presumed viral myocarditis with ongoing inflammatory damage to the myocardium that is the focus of the current study.

To date, no specific therapy has been developed with proven efficacy in patients with acute myocarditis. All patients with acute myocarditis should receive guideline‐specified medical treatment for HF as indicated by the clinical presentation. ⁶ This includes ACE inhibitors, ARBs or ARB/NEP inhibitors, beta‐blockers, diuretics (including aldosterone inhibitors) and SGLT2 inhibitors. If the presentation is one of fulminant HF, then inotropic support and possibly mechanical circulatory support or veno‐arterial extracorporeal life support are indicated. ⁷ Steroid‐based immune suppressive immunomodulating therapies are recommended only for endomyocardial biopsy (EMB)‐proven giant cell or eosinophilic myocarditis.

A number of therapeutic approaches have been tested in patients with myocarditis, although the condition remains a therapeutic dilemma. ¹ Although intense inflammation in the myocardium serves to eliminate the virus quickly, thereby avoiding more extensive tissue damage, if the inflammation persists despite viral elimination, continued myocardial damage can occur. An effective anti‐inflammatory therapy, while limiting tissue damage mediated by inflammation, must not facilitate, for example, progressive viral replication. In a trial in patients with chronic HF (>6 months) with evidence of myocardial inflammation in the absence of continued viral genome persistence, immunosuppressive therapy with cortisone and azathioprine had beneficial effects. ⁸ The LVEF improved in almost 90% of the treated group versus none in the placebo group and showed a long‐term benefit over 20 years. ⁹ In a long‐term (follow‐up of 100 months) registry, the authors found that immunosuppressive therapy was associated with better heart transplant‐free survival. ¹⁰ Unfortunately, further research has not confirmed these positive findings. Mason et al. assigned 111 patients with myocarditis and LV dysfunction to either conventional therapy alone or combined with immunosuppressive therapy with prednisone and either cyclosporin or azathioprine. The primary outcome was the change in LVEF over a 24‐week period. This study found that LV function improved regardless of the treatment received and that it did not support the routine treatment of myocarditis with immunosuppressive agents. ¹¹

Some therapies have been aimed at eliminating the virus in patients without acute myocarditis or myocardial inflammation. Because enterovirus and adenoviruses directly infect the cardiomyocytes, viral clearance with a 6‐month course of Interferon beta was associated with an improvement in LVEF and NYHA status. ¹² Those with viral clearance had a better survival than those with viral persistence. ¹³ Unfortunately, to date, randomized trials have not established anti‐viral therapy as efficacious for acute myocarditis. ⁶

Approaches that have not proven efficacious include intra‐venous immunoglobulin ¹⁴ ; however, this may be effective for certain viral subtypes. Other immunosuppressive and immunomodulatory approaches are being tested. ⁶ Anakinra, an interleukin‐1 receptor antagonist used in the therapy of connective tissue disorders, has recently been evaluated. Patients with acute myocarditis were randomized within 72 h of the diagnosis to either anakinra or placebo. The endpoints were event‐free survival, hospitalization for HF, chest pain requiring medication, LVEF >50%, ventricular arrhythmia, ventricular tachycardia (VT) or ventricular fibrillation (VF). No benefit was seen after 28 days of follow‐up. ¹⁵

In summary, there is, as yet, no accepted specific therapy for patients who present with acute myocarditis.

The ARCHER trial is assessing if a pharmaceutically produced cannabidiol formulation, by modulating the immune response in the setting of acute myocarditis, will have beneficial effects in this patient population. We, and others, have demonstrated the significant anti‐inflammatory response resulting from the administration of cannabidiol in a number of models of cardiovascular disease. Indeed, a recent study in a model of acute pericarditis has demonstrated that CBD inhibits the development of the NLRP3 inflammasome, a mechanism of inflammation that is important in both the cardiovascular and neurologic systems. ¹⁶ , ¹⁷