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. The duration of problems can vary from hours to months. Complications may include heart failure due to dilated cardiomyopathy or cardiac arrest. Myocarditis is most often due to a viral infection. Other causes include bacterial infections, certain medications, toxins and autoimmune disorders. A diagnosis may be supported by an electrocardiogram (ECG), increased troponin, heart MRI, and occasionally a heart biopsy. An ultrasound of the heart is  important to rule out other potential causes such as heart valve problems. Treatment depends on both the severity and the cause. Medications such as ACE inhibitors, beta blockers, and diuretics are often used. A period of no exercise is typically recommended during recovery. Corticosteroids or intravenous immunoglobulin (IVIG) may be useful in certain cases. In severe cases an implantable cardiac defibrillator or heart transplant may be recommended. In 2013, about 1.5 million cases of acute myocarditis occurred. While people of all ages are affected, the young are most often affected. It is slightly more common in males than females. Most  cases are mild. In 2015 cardiomyopathy, including myocarditis, resulted in 354,000 deaths up from 294,000 in 1990. The initial descriptions of the condition are from the mid-1800s. Signs and symptoms. The signs and symptoms associated with myocarditis are varied, and relate either to the actual inflammation of the myocardium or to the weakness and dysfunction of the heart muscle that is secondary to the inflammation. While myocarditis may develop over periods ranging from hours to months, patients typically present with signs and symptoms that resemble heart failure, including the following: Since myocarditis is often due to a viral illness, many  patients experience symptoms consistent with a recent viral infection including a fever, rash, loss of appetite, abdominal pain, vomiting, diarrhea, joint pains, and easily becoming tired. Additionally, myocarditis is often associated with pericarditis, and many people with myocarditis present with signs and symptoms that suggest myocarditis and pericarditis at the same time. Children primarily present with the aforementioned symptoms associated with a viral infection. Since they overlap with many other illnesses, this can make it more challenging to diagnose myocarditis in younger patients. Later stages of the illness can involve the respiratory system and lead to increased work of breathing . These are often mistaken for asthma. Myocarditis can be distinguished as either fulminant or acute based on the severity of symptoms on presentation, as well as the time course over which symptoms develop and persist. This categorization can help predict the treatment, outcomes, and complications of myocarditis. Fulminant myocarditis is defined as sudden and severe myocarditis that is associated with signs and symptoms of heart failure while at rest. More specifically, fulminant myocarditis is characterized by a distinct, rapid onset of severe heart failure symptoms, such as shortness of breath and chest pain, that develop over the course of hours  to days. Additionally, treatment requires the use of medications or mechanical devices to improve heart function. Acute non-fulminant myocarditis has a less distinct onset in contrast to fulminant myocarditis, and evolves over days to months. While the symptoms of acute myocarditis overlap with those of fulminant myocarditis, they do not typically occur at rest, and treatment does not require the use of mechanical circulatory support. Causes. While many causes of myocarditis are known, there are many cases in which a causative agent cannot be identified. In Europe and North America, viruses are common culprits. Worldwide, however, the most  common cause is Chagas disease, an illness endemic to Central and South America that results from infection with the protozoan "Trypanosoma cruzi". Overall, myocarditis can be caused by infections, immune conditions, toxins, drug reactions, and physical injuries to the heart. These different etiologies are detailed below. Infections. The most common causes of myocarditis are infectious organisms. Viral infections are the most common cause in developed countries, with a majority of cases being caused by those with single-stranded RNA genetic information such as Coxsackie viruses (especially Coxsackie B3 and B5). Globally, Chagas disease is the leading cause of myocarditis, which  results from infection with the protozoan "Trypanosoma cruzi." Bacteria can also result in myocarditis, although it is rare in patients with normal heart function and without a preexisting immunodeficiency. A list of the most relevant infectious organisms is below. Mechanism. 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. 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. The mechanism by which coxsackie B viruses (CBVs) trigger inflammation is believed to be through the recognition of CBV virions by Toll-like receptors. The binding of the SARS -CoV-2 virus through ACE2 receptors present in heart tissue may be responsible for direct viral injury leading to myocarditis. In a study done during the SARS outbreak,  SARS virus RNA  was ascertained in the autopsy of heart specimens in 35% of the patients who died due to SARS. It was also observed that an already diseased heart has increased expression of ACE2 receptor contrasted to healthy individuals. 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. Diagnosis. 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. Myocardial inflammation can be suspected on the basis of electrocardiographic (ECG) results, elevated C-reactive protein (CRP) and/or erythrocyte sedimentation rate (ESR), and increased IgM (serology) against viruses known to affect the myocardium. Markers of myocardial damage (troponin or creatine kinase cardiac isoenzymes) are  elevated. The ECG findings most commonly seen in myocarditis are diffuse T wave inversions; saddle-shaped ST-segment elevations may be present (these are also seen in pericarditis). 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. 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. Consensus criteria for the diagnosis of myocarditis by CMR were published in 2009. Treatment. While myocarditis  has many etiologies and a variable constellation of signs and symptoms, there are few causes that are treatable and thus the main focus is on symptom management. In cases with biopsy-proven myocarditis, the causative cell type can indicate potentially beneficial treatments. These treatments typically consist of corticosteroids, or medications with known benefits in certain autoimmune and systemic conditions. In a majority of cases, the main therapies are used to support patients and are dependent on the severity of symptoms and the time course across which myocarditis develops. Supportive therapies can be divided into two broad categories, medications and mechanical  support, since there has yet to be any demonstrated benefits from complementary therapies. Medication. The specific medications that are used to support patients are directly related to the cause of the symptom or sign. Just as the symptoms of myocarditis mirror those of congestive heart failure, so too do the therapies. Additionally, the order in which therapies are used depends on the degree of heart dysfunction, with stabilization of patient blood pressure and breathing taking highest priority when present. This can involve the use of inotropes, or medications that make the heart contract with greater force, as well as antiarrhythmic  drugs such as adenosine or carvedilol. In patients that have stable and adequate heart function, further treatments are based on heart failure guidelines. ACE inhibitors can have a protective benefit to the heart, so they are typically used in any patient with symptomatic myocarditis. Simultaneously, beta blockers are used in patients that can tolerate their heart beating at a slower rate. Shortness of breath at rest and swelling can be relieved with diuretics such as furosemide, and the addition of aldosterone receptor blockers can augment the diuresis while preventing the excess loss of potassium. In patients with symptoms while resting , additional medications can be added such as digoxin. Mechanical support. Mechanical support is used in cases of myocarditis in which medications alone do not lead to adequate heart function and the body requires additional support to achieve organ perfusion. Myocarditis cases that require mechanical circulatory support are categorized as fulminant by definition. People that require additional support with their heart function can benefit from the use of ventricular assist devices like intra-aortic balloon pumps. In people with myocarditis severe enough to cause cardiac arrest, extracorporeal membrane oxygenation (ECMO) is used to adequately pump blood and provide oxygen if needed . Both ventricular assist devices and ECMO can be used as bridge therapy until heart transplantation in patients that are candidates. Heart transplantation is reserved for those that do not respond to the aforementioned conventional medical therapies. Prognosis. 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. 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. Electrocardiogram findings of ST elevations with upward concavity and an early repolarization pattern, however, were associated with a better cardiovascular prognosis in general. 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. A similar relationship was found between a left ventricular ejection fraction < 50%, increased mortality, and increased major adverse cardiovascular events. 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 inhomogeneity in the study populations. And one has also to distinguish between studies about myocarditis in general and "fulminant" myocarditis. Epidemiology. The exact incidence of myocarditis is unknown since many cases are not associated with any symptoms. However, in series of routine autopsies, 1–9% of all patients had evidence of myocardial inflammation. The prevalence rate of myocarditis is estimated to be about 22 cases per 100,000 persons annually. Fulminant myocarditis, the most severe subtype, has been shown to occur in  up to 2.5% of known myocarditis presentations. When looking at different causes of myocarditis, viral infection is the most prevalent, especially in children; however, the prevalence rate of myocarditis is often underestimated since the condition is easily overlooked. Viral myocarditis being an outcome of viral infection depends heavily on genetic host factors and the pathogenicity unique to the virus. If one tests positive for an acute viral infection, clinical developments have discovered that 1-5% of said population may show some form of myocarditis. One notable instance of viral myocarditis is the involvement of the SARS-CoV-2 virus; myocarditis from  SARS-CoV-2 is associated with a spectrum of severities from asymptomatic to fulminant, and is a complication in approximately 2-7% of COVID-19 cases. In regard to the population affected, myocarditis is more common in pregnant women, children, and those who are immunocompromised. Myocarditis, however, has shown to be more common in the male population than in the female. Multiple studies report a 1:1.3-1.7 female-male ratio of prevalence of myocarditis. In young adults, up to 20% of all cases of sudden death are due to myocarditis. Young males specifically have a higher incidence rate than any other population  due to their testosterone levels creating a greater inflammatory response that increases the chance of cardiac pathologies. While males tend to have a higher risk of developing myocarditis, females tend to display more severe signs and symptoms, such as ventricular tachycardia and ventricular fibrillation, but do so at an older age. Among patients with HIV, myocarditis is the most common cardiac pathological finding at autopsy, with a prevalence of 50% or more. Myocarditis is the third most common cause of death among young adults with a cumulative incidence rate globally of 1.5 cases per 100,000 persons annually. Myocarditis accounts for  approximately 20% of sudden cardiac death in a variety of populations, including adults under the age of 40, young athletes, United States Air Force recruits, and elite Swedish orienteers. With individuals who develop (fulminant?) myocarditis, the first year is difficult as a collection of cases have shown there is a 20% mortality rate. History. Cases of myocarditis have been documented as early as the 1600s, but the term "myocarditis", implying an inflammatory process of the myocardium, was introduced by German physician Joseph Friedrich Sobernheim in 1837. However, the term has been confused with other cardiovascular conditions, such as hypertension and  ischemic heart disease. Following admonition regarding the indiscriminate use of myocarditis as a diagnosis from authorities such as British cardiologist Sir Thomas Lewis and American cardiologist and a co-founder of the American Heart Association Paul White, myocarditis was under-diagnosed. 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.