Myocarditis
Myocarditis, also known as inflammatory cardiomyopathy, is an acquired cardiomyopathy due to inflammation of the heart muscle. Symptoms can include shortness of breath, chest pain, decreased ability to exercise, and an irregular heartbeat.[1] The duration of problems can vary from hours to months. Complications may include heart failure due to dilated cardiomyopathy or cardiac arrest.[1]
Myocarditis
Inflammatory cardiomyopathy (infectious)
Shortness of breath, chest pain, decreased ability to exercise, irregular heartbeat[1]
Hours to months[1]
Usually viral infection, also bacterial infections, certain medications, autoimmune disorders[1][2]
Electrocardiogram, blood troponin, heart MRI, heart biopsy[1][2]
Medications, implantable cardiac defibrillator, heart transplant[1][2]
Variable[3]
2.5 million with cardiomyopathy (2015)[4]
354,000 with cardiomyopathy (2015)[5]
Myocarditis is most often due to a viral infection.[1] Other causes include bacterial infections, certain medications, toxins and autoimmune disorders.[1][2] A diagnosis may be supported by an electrocardiogram (ECG), increased troponin, heart MRI, and occasionally a heart biopsy.[1][2] An ultrasound of the heart is important to rule out other potential causes such as heart valve problems.[2]
Treatment depends on both the severity and the cause.[1][2] Medications such as ACE inhibitors, beta blockers, and diuretics are often used.[1][2] A period of no exercise is typically recommended during recovery.[1][2] Corticosteroids or intravenous immunoglobulin (IVIG) may be useful in certain cases.[1][2] In severe cases an implantable cardiac defibrillator or heart transplant may be recommended.[1][2]
In 2013, about 1.5 million cases of acute myocarditis occurred.[6] While people of all ages are affected, the young are most often affected.[7] It is slightly more common in males than females.[1] Most cases are mild.[2] In 2015 cardiomyopathy, including myocarditis, resulted in 354,000 deaths up from 294,000 in 1990.[8][5] The initial descriptions of the condition are from the mid-1800s.[9]
Mechanism[edit]
Most forms of myocarditis involve the infiltration of heart tissues by one or two types of pro-inflammatory blood cells, lymphocytes and macrophages plus two respective descendants of these cells, NK cells and macrophages. Eosinophilic myocarditis is a subtype of myocarditis in which cardiac tissue is infiltrated by another type of pro-inflammatory blood cell, the eosinophil. Eosinophilic myocarditis is further distinguished from non-eosinophilic myocarditis by having a different set of causes and recommended treatments.[34][18]
The pathophysiology of viral myocarditis is not well understood, but it is believed to involve cardiotropic viruses (viruses with a high affinity for the heart muscle) gaining entry to cardiac muscle cells, usually via binding to a transmembrane receptor.[29] Over approximately the next 1–7 days the virus replicates and causes inflammation leadings to necrosis and apoptosis of cardiac muscle cells (myocytes) and activation of the innate immune system.[29] Over the next 1–4 weeks, viral replication continues with subsequent activation of the acquired immune system leading to T cell infiltration and the formation of antibodies, including possibly auto-antibodies.[29] Over the next few months to years, this process either resolves and concludes with viral clearance or it may progress to cause permanent heart damage such as dilated cardiomyopathy, ventricular dysfunction or other cardiomyopathies.[29] Coxsackie B, specifically B3 and B5, has been found to interact with coxsackievirus-adenovirus receptor (CAR) and decay-accelerating factor (DAF). However, other proteins have also been identified that allow Coxsackieviruses to bind to cardiac cells. The natural function of CAR and mechanism that the Coxsackievirus uses to infect the cardiac muscle is still unknown.[17] The mechanism by which coxsackie B viruses (CBVs) trigger inflammation is believed to be through the recognition of CBV virions by Toll-like receptors.[17]
The binding of many types of coronaviruses, including the SARS-CoV-2 virus, through ACE2 receptors present in heart muscle may be responsible for direct viral injury leading to myocarditis.[23] In a study done during the 2002-2004 SARS outbreak, SARS viral RNA was detected in the autopsy of heart specimens in 35% of the patients in the Toronto, Canada area who had died due to SARS.[35] It was also observed that an already diseased heart has increased expression of ACE2 receptor contrasted to healthy individuals which may lead to greater viral infiltration in the heart muscle. Hyperactive immune responses in COVID-19 patients may lead to the initiation of the cytokine storm. This excess release of cytokines may lead to myocardial injury.[23] In addition to direct cardiac myocyte (heart muscle cell) damage due to SARS-CoV-2 viral infiltration and inflammation, there are other suspected mechanisms that Covid-19 may indirectly cause myocarditis. During COVID-19, the other indirect mechanisms thought to contribute to myocarditis include: oxygen supply-demand mismatch to the heart muscle leading to myocardial (heart muscle) injury; microvascular thrombi, or blood clots in the small blood vessels of the heart causing injury; the systemic hyperinflammatory state in Covid-19 leading to heart muscle injury; or the virus causing indirect damage to the heart by inducing auto-immune mediated damage to the heart muscle (and frequently other organs).[29]
Myocarditis refers to an underlying process that causes inflammation and injury of the heart. It does not refer to inflammation of the heart as a consequence of some other insult. Many secondary causes, such as a heart attack, can lead to inflammation of the myocardium and therefore the diagnosis of myocarditis cannot be made by evidence of inflammation of the myocardium alone.[36][37]
Myocardial inflammation can be suspected on the basis of elevated inflammatory markers including C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), or an increased IgM (serology) against viruses known to affect the myocardium. Markers of myocardial damage (troponin or creatine kinase cardiac isoenzymes) are elevated.[10] The CRP and ESR are sometimes elevated in myocarditis but they are not specific as they may be elevated due to many other causes.[29] Similarly, CK may be elevated in myocarditis but is also non-specific, as it may be elevated in myositis (skeletal muscle injury).[29] High sensitivity troponin is usually elevated in myocarditis and this marker is very specific to myocardial (heart muscle) injury.[29]
Myocardial inflammation may also be suspected based on ECG findings, but these findings are not specific to myocarditis.[38] The ECG finding most commonly seen in myocarditis is sinus tachycardia with non-specific ST or T wave changes.[38] But other findings that may be seen in perimyocarditis (a combination of pericarditis and myocarditis) include PR segment depression, PR segment depression with associated ST segment elevation, diffuse ST segment elevation (in a pericarditis pattern).[38] ST segment elevation was seen in 62% of people with myocarditis.[29] The presence of Q waves, a widened QRS complex, prolongation of the QT interval, high degree AV nodal blockade, and ventricular tachyarrhythmias are associated with a poor prognosis when seen on ECG in people with myocarditis.[38]
The gold standard is the biopsy of the myocardium, in general done in the setting of angiography. A small tissue sample of the endocardium and myocardium is taken and investigated. The cause of the myocarditis can be only identified by a biopsy. Endomyocardial biopsy samples are assessed for histopathology (how the tissue looks like under the microscope): myocardial interstitium may show abundant edema and inflammatory infiltrate, rich in lymphocytes and macrophages. Focal destruction of myocytes explains the myocardial pump failure.[10] In addition samples may be assessed with immunohistochemistry to determine which types of immune cells are involved in the reaction and how they are distributed. Furthermore, PCR and/or RT-PCR may be performed to identify particular viruses. Finally, further diagnostic methods like microRNA assays and gene-expression profile may be performed.
Cardiac magnetic resonance imaging (cMRI or CMR) has been shown to be very useful in diagnosing myocarditis by visualizing markers for inflammation of the myocardium.[39] Cardiac MRI is most sensitive when performed 2–3 weeks after the initial clinical presentation of myocarditis and may be repeated 6–12 months after onset to monitor the evolution of disease or response to treatment.[29] The Lake Louise Criteria (established in 2009) are a commonly used MRI criteria to establish the diagnosis of myocarditis in suspected cases.[40] The Lake Louise Criteria include increased signal intensity after gadolinium contrast enhancement (a sign of hyperemia, or increased blood flow to damaged tissue), increased myocardial T2 relaxation time or an increased T2 signal intensity (which are signs of tissue edema or swelling), and late gadolinium contrast enhancement (which is a sign of tissue necrosis (tissue damage) or fibrosis (scarring)).[29] In 2018, additional radiographic MRI criteria were added, including increased T1 signal intensity and increased extracellular volume (both of which being signs of myocardial injury).[29] The original 2009 Lake Louise Criteria had a 74% sensitivity and 86% specificity in the diagnosis of myocarditis, but when adding the 2018 update to the criteria (in which T1 signal intensity was found to have high diagnostic sensitivity), the sensitivity and specificity in the diagnosis of myocarditis increased to 88% and 96% respectively.[29][41] Cardiac MRI, if available, is recommended in all cases of suspected myocarditis.[29]
Prognosis[edit]
The prognosis associated with myocarditis is stratified by the severity and time course along which symptoms develop. In addition to symptom severity, there are also several indicators of heart function that can be used to predict patient outcomes, many of which are part of the standard evaluation of patients presenting with cardiovascular dysfunction. Most people with myocarditis have an uncomplicated, self-limited and mild course while making a full recovery.[29] However, those with myocarditis that present with a decreased ejection fraction, or those who present with heart failure, advanced atrioventricular block, with sustained ventricular arrhythmias or with hemodynamic instability have a worse prognosis with an increased risk of death or need for heart transplantation.[29]
An electrocardiogram is one of the most common screening tools used in cases of suspected cardiac pathology, such as myocarditis. The findings that correlate with poorer outcomes are non-specific and include widened QRS complexes and QT intervals, partial or complete atrial-ventricular heart block, and malignant ventricular arrhythmias like sustained ventricular tachycardia or ventricular fibrillation.[48] Electrocardiogram findings of ST elevations with upward concavity and an early repolarization pattern, however, were associated with a better cardiovascular prognosis in general.[48]
In cases of acute myocarditis, cardiac magnetic resonance imaging can reveal several prognostic indicators that, similar to ECGs, are non-specific and reflect poorer cardiac physiology. Late gadolinium enhancement on cardiac MRI demonstrates perturbations in extracellular volume as a result of cell necrosis or edema, and is significantly associated with increases in all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events. The association was strongest with any late gadolinium enhancement, but remained true for findings of anterolateral-specific enhancement.[49][50] A similar relationship was found between a left ventricular ejection fraction < 50%, increased mortality, and increased major adverse cardiovascular events.[51]
Myocarditis has been reported to be a major cause of sudden cardiac death (SCD) in infants, adolescents, and young adults, but the reported rates show wide variation (1 to 14 percent) among young people depending on differences in SCD definition and classification/ definition of myocarditis post-mortem as well as heterogeneity of study populations.[52]
In fulminant myocarditis, in which an inflammatory cytokine storm occurs, cardiac functions decline rapidly and the death rate is high.[14]
History[edit]
Cases of myocarditis have been documented as early as the 1600s,[65] but the term "myocarditis", implying an inflammatory process of the myocardium, was introduced by German physician Joseph Friedrich Sobernheim in 1837.[66] However, the term has been confused with other cardiovascular conditions, such as hypertension and ischemic heart disease.[67] Following admonition regarding the indiscriminate use of myocarditis as a diagnosis from authorities such as British cardiologist Sir Thomas Lewis and American cardiologist and co-founder of the American Heart Association Paul White, myocarditis was under-diagnosed.[67]
Although myocarditis is clinically and pathologically clearly defined as "inflammation of the myocardium", its definition, classification, diagnosis, and treatment are subject to continued controversy, but endomyocardial biopsy has helped define the natural history of myocarditis and clarify clinicopathological correlations.[68]