| disease | Viral Myocarditis |
Myocarditis refers to localized or diffuse acute, subacute, or chronic inflammatory changes in the myocardium. It is often part of various systemic diseases. Grade I myocarditis has fewer clinical manifestations and is more difficult to diagnose, so the pathological diagnosis rate is much higher than the clinical incidence. In recent years, with a deeper understanding of the etiology of myocarditis and improvements in diagnostic methods, myocarditis has become one of the common heart diseases and is receiving increasing attention.
bubble_chart Etiology
Various viruses can cause myocarditis, with the most common being those that cause intestinal and upper respiratory infections, such as enteroviruses. Enteroviruses are picornaviruses, among which Coxsackie, ECHO, and polioviruses are the primary viruses causing myocarditis. Myxoviruses like influenza, parainfluenza, and respiratory syncytial viruses are also frequently implicated in myocarditis. Adenoviruses occasionally cause myocarditis as well. Additionally, measles, mumps, Japanese encephalitis, hepatitis, and cytomegalovirus can also lead to myocarditis. Clinically, the vast majority of viral myocarditis cases are caused by Coxsackie and ECHO viruses. Coxsackie virus group B is the leading pathogen of human myocarditis, with types 2 and 4 being the most common, followed by types 5, 3, and 1. Group A types 1, 4, 9, 16, and 23 tend to infect infants and occasionally invade adult myocardium.
Based on disease etiology, myocarditis can be classified into the following three categories:
(1) Myocarditis occurring during the course of infectious diseases. The causative pathogens can be bacteria, viruses, fungi, rickettsiae, spirochetes, or Chinese Taxillus Herb parasites. Bacterial infections, particularly diphtheria, are notable as one of the most severe complications of the disease; myocarditis is also common in cold-damage diseases. During bacterial infections, the myocardium can be damaged by bacterial toxins. Bacterial endocarditis or myocarditis can extend to the myocardium, accompanied by myocarditis, with staphylococci, streptococci, or pneumococci being the primary pathogens. Meningococcal bacteremia and septicemia may occasionally invade the myocardium, causing inflammation. Various fungi, such as actinomycetes, Candida albicans, Aspergillus, Histoplasma, and Cryptococcus, can also cause myocardial inflammation, though these cases are rare. Protozoal myocarditis is mainly seen in South American trypanosomiasis and toxoplasmosis. Rickettsial diseases like macula and papule cold-damage disease can also involve myocardial inflammation. Among spirochetal infections, leptospirosis-related myocarditis is not uncommon, and syphilis can lead to gumma formation in the myocardium. In recent years, the incidence of viral myocarditis has increased significantly, garnering considerable attention. It is currently the most common type of myocarditis in China, while myocarditis caused by fungi, Chinese Taxillus Herb parasites, rickettsiae, or spirochetes is far less common than viral and bacterial myocarditis.
(2) Myocarditis caused by allergies or hypersensitivity reactions. Based on current knowledge, the pathogenesis of wind-dampness heat is most likely due to hypersensitivity reactions, and wind-dampness myocarditis falls into this category.(3) Myocarditis caused by chemicals, physical factors, or drugs. Chemicals or drugs such as emetine, trivalent antimony, and doxorubicin, or electrolyte imbalances like potassium deficiency or excess, can cause myocardial damage, with pathological inflammatory changes. Excessive radiation to the cardiac region can also induce similar inflammatory changes.
From animal experiments, clinical and virological studies, and pathological observations, the following two mechanisms have been identified:
(1) Direct viral effect In experiments, injecting the virus into the bloodstream can cause myocarditis. During the acute phase, primarily within the first 9 days of onset, the virus can be isolated from the myocardium of patients or animals, with positive results from viral fluorescent antibody tests or the observation of viral particles under electron microscopy. After infecting myocardial cells, the virus produces cytolytic substances, leading to cell lysis.
(2) Immune response In experiments and human cases of viral myocarditis, the virus can no longer be detected in the myocardium after 9 days of onset, yet myocardial inflammation persists. Some patients exhibit mild symptoms of viral infection but severe myocarditis, while others develop myocarditis symptoms only after a period of other viral infection symptoms. In some patients, antigen-antibody complexes may be found in the myocardium. These observations suggest the involvement of immune mechanisms. In experiments, mouse myocardial cells infected with a small amount of Coxsackie virus showed insignificant cytotoxicity. However, when homologous immune spleen cells were added, cytotoxicity increased. If immune spleen cells were pretreated with anti-thymocyte antibody and complement, cytotoxicity did not increase. Conversely, pretreatment with Coxsackie B antibody and complement enhanced cytotoxicity. These findings indicate the presence of cell-mediated immune mechanisms in viral myocarditis. Studies also suggest that cytotoxicity is primarily mediated by T lymphocytes. Clinically, in patients with persistent viral myocarditis, E-rosette formation, lymphocyte transformation rate, and complement C3 levels are lower than in healthy individuals, while the detection rates of antinuclear antibodies, anti-myocardial antibodies, and anti-complement antibodies are higher, indicating impaired immune function in viral myocarditis. Recent studies have found that the activity of natural killer cells and α-interferon are significantly lower than normal in viral myocarditis, while γ-interferon is higher than normal, reflecting dysregulation of cellular immunity. In mouse experimental myocarditis, administering the immunosuppressant cyclosporine A early in the infection worsened the condition and increased mortality, whereas administration after 1 week reduced mortality.
The above data suggest that viral myocarditis is primarily driven by direct viral effects in the early stages, followed by immune responses later.bubble_chart Pathological Changes
The extent of lesions varies, ranging from diffuse to localized. Depending on the course of the disease, they can be acute or chronic. In severe cases, the myocardium appears very loose, gray or yellow, with dilated cardiac chambers upon gross examination. In milder cases, no abnormalities are detected macroscopically, and diagnosis relies solely on microscopic findings. Pathological examination must include multiple sections to avoid missing the lesions. Microscopically, cellular infiltrates, predominantly mononuclear cells, can be observed between myocardial fibers and in the connective tissue surrounding blood vessels. Myocardial cells may exhibit degeneration, dissolution, or necrosis. If the lesions are located in the subpericardial region, pericarditis may develop, resulting in viral pericardial myocarditis. The lesions may involve both the myocardium and interstitium, as well as the cardiac pacing and conduction systems, such as the sinoatrial node, atrioventricular node, atrioventricular bundle, and bundle branches, forming the basis for arrhythmias. The more virulent the virus, the more extensive the lesions. In experimental myocarditis, myocardial necrosis can be replaced by fibrous tissue after considerable effort.
bubble_chart Clinical Manifestations
It depends on the extent and location of the lesion. Severe cases can lead to sudden death, while mild cases may have almost no symptoms. It can occur in both the elderly and children, but is more common in young people. Males are more affected than females.
(1) Symptoms The symptoms of myocarditis may appear during the symptomatic phase or the stage of convalescence of the primary disease. If they occur during the symptomatic phase of the primary disease, their manifestations may be masked by the primary disease. Most patients experience symptoms such as fever, general body aches, sore throat, diarrhea, etc., before the onset, reflecting a systemic sexually transmitted disease infection. However, some patients may have mild or insignificant primary disease symptoms, which may only be noticed upon careful questioning, while the symptoms of myocarditis are more pronounced. Patients with myocarditis often complain of chest tightness, dull pain in the precordial area, palpitations, lack of strength, nausea, and dizziness. Among clinically diagnosed cases of myocarditis, about 90% present with arrhythmia as the main or first symptom, and a few patients may experience syncope or Adams-Stokes syndrome as a result. A very small number of patients may rapidly develop heart failure or cardiogenic shock after onset.(2) Signs
1. Cardiac enlargement Mild cases may not show cardiac enlargement, but generally, there is temporary enlargement that resolves shortly. Significant cardiac enlargement reflects widespread and severe myocarditis.
2. Changes in heart rate A heart rate that is disproportionately rapid relative to body temperature or abnormally slow are both suspicious signs of myocarditis.
3. Changes in heart sounds The first heart sound at the apex may be diminished or split. Heart sounds may resemble fetal heart sounds. The presence of a pericardial friction rub indicates pericarditis.
4. Murmurs A blowing systolic murmur or diastolic murmur may be heard at the apex. The former is caused by fever, anemia, or cardiac chamber enlargement, while the latter results from relative mitral stenosis due to left ventricular enlargement. The intensity of the murmurs does not exceed grade 3. They disappear as myocarditis improves.
5. Arrhythmias Extremely common, with various types possible. Atrial and ventricular premature beats are the most frequent, followed by atrioventricular block. Additionally, atrial fibrillation and sick sinus syndrome may occur. Arrhythmias are one of the causes of sudden death.
6. Heart failure Patients with severe diffuse myocarditis may develop acute heart failure, which is a failure of the myocardial pumping function. Both left and right heart failure occur simultaneously, leading to excessively low cardiac output. Therefore, in addition to the general manifestations of heart failure, cardiogenic shock is prone to occur.
bubble_chart Auxiliary Examination
1. The white blood cell count may increase, the erythrocyte sedimentation rate may accelerate during the acute phase, and serum transaminase and creatine phosphokinase levels may rise in some patients, reflecting myocardial necrosis.
2. Electrocardiogram ① ST-T changes: Inverted or diminished T waves are common, sometimes showing ischemic T wave changes; ST segments may exhibit grade I displacement. ② Arrhythmias: Besides sinus tachycardia and sinus bradycardia, ectopic rhythms and conduction blocks are common. Atrial, ventricular, and atrioventricular junctional premature beats can all occur, with about two-thirds of patients primarily exhibiting ventricular premature beats. Premature beats may have fixed coupling intervals, but most do not, and some meet the criteria for parasystole. These premature beats without fixed coupling intervals may reflect ectopic excitability. Patients may show no other findings besides premature beats, possibly originating from focal sexually transmitted disease changes. Premature beats can be unifocal or multifocal. Supraventricular or ventricular tachycardia is relatively rare, but ventricular tachycardia may lead to syncope. Atrial fibrillation and flutter are also observed, with flutter being relatively less common. The aforementioned rapid rhythms may occur in short bursts or persist continuously. Ventricular fibrillation is rare but can be a cause of sudden death. Grade I to grade III sinoatrial, atrioventricular, bundle branch, or fascicular blocks may all occur, with about one-third of patients rapidly progressing to grade III atrioventricular block after onset, becoming another mechanism for sudden death. The various arrhythmias mentioned can occur in combination. Arrhythmias may appear during the acute phase and disappear during the stage of convalescence, or they may persist due to scar formation. Scar foci are one of the bases for recurrent premature beats.
3. X-ray examination Focal myocarditis shows no abnormal changes. Patients with diffuse myocarditis or those complicated by pericarditis may exhibit cardiac shadow enlargement, weakened heartbeats, and in severe cases, pulmonary congestion or pulmonary edema.
4. Echocardiography Findings may include left ventricular systolic or diastolic dysfunction, segmental or regional wall motion abnormalities, increased wall thickness, enhanced and uneven myocardial echo reflection, right ventricular dilation, and abnormal motion.
5. Radionuclide examination Two-thirds of patients may show a reduced left ventricular ejection fraction.
6. Virological tests These include isolating the virus from throat swabs, feces, or myocardial tissue, detecting specific antiviral antibody titers in serum, identifying specific antigens in myocardial biopsy specimens via immunofluorescence or viral particles under electron microscopy, and detecting viral RNA in feces, serum, or myocardial tissue using polymerase chain reaction.
The diagnosis of viral myocarditis must be established based on evidence of myocarditis and viral infection. Chest tightness and palpitation often suggest cardiac involvement, while cardiac enlargement, arrhythmia, or heart failure indicate significant cardiac damage. ST-T changes on the electrocardiogram (ECG), ectopic rhythms, or conduction disturbances reflect the presence of myocardial lesions. Evidence of viral infection includes the following: ① Fever, diarrhea, or flu-like symptoms followed shortly by cardiac symptoms or ECG changes. ② Positive serum viral neutralizing antibody test results. Since Coxsackie B virus is the most common, neutralizing antibodies for this group of viruses are typically tested. Blood samples are taken early in the illness and again 2–4 weeks later. If the antibody titer shows a fourfold increase or one of the titers is ≥1:640, it can be considered evidence of recent infection. ③ Viral isolation from throat or anal swabs, if positive, is supportive, though some healthy individuals may also test positive. The significance must be interpreted in conjunction with positive neutralizing antibody results. ④ Detection of viral RNA in feces, serum, or myocardial tissue using polymerase chain reaction (PCR). ⑤ Myocardial biopsy: Viral testing of the obtained tissue can aid in the diagnosis of myocarditis.
Appendix: Reference diagnostic criteria for acute sexually transmitted disease viral myocarditis in adults proposed at the 1995 National Symposium on Myocarditis and Cardiomyopathy
(1) Cardiac manifestations such as severe lack of strength (reduced cardiac output), markedly diminished first heart sound, diastolic gallop rhythm, pericardial friction rub, cardiac enlargement, congestive heart failure, or Adams-Stokes syndrome occurring within 1–3 weeks after an upper respiratory tract infection, diarrhea, or other viral infection, or during the acute phase.
(2) Various new-onset arrhythmias and/or ECG abnormalities appearing within 1–3 weeks after the aforementioned infection or concurrently with the onset of illness, with the following ECG changes observed before taking antiarrhythmic medications:
1. Atrioventricular block, sinoatrial block, or bundle branch block.
2. Horizontal or downward-sloping ST-segment depression ≥0.05 mV in two or more leads, or abnormal ST-segment elevation or pathological Q waves in multiple leads.
3. Multifocal or paired ventricular premature beats, automatic atrial or junctional tachycardia, sustained or non-sustained paroxysmal ventricular tachycardia, atrial or ventricular flutter or fibrillation.
4. Inversion, flattening, or reduction of T waves to <1/10 of the R wave amplitude in two or more leads where R waves are dominant.
5. Frequent atrial or ventricular premature beats.
Note: The presence of any one of items 1–3 is sufficient for diagnosis. For items 4 or 5, if there is no clear history of viral infection, one of the following criteria must be met to support the diagnosis:
1. One of the following etiological evidences:
(1) A fourfold increase in the titer of the same viral antibody between the first and second serum samples (taken at least 2 weeks apart), or a single antibody titer ≥1:640 is considered positive; a titer of 1:320 is considered suspicious (if the baseline is 1:32, then ≥1:256 is positive and 1:128 is suspicious, depending on laboratory standards).
(2) Viral-specific IgM ≥1:320 is considered positive (according to laboratory diagnostic standards, but strict quality control is required). If both (1) and (2) are accompanied by detection of the same viral gene, it further supports recent viral infection.
(3) Detection of enterovirus nucleic acid in blood alone may indicate other enteroviral infections.
(4) Detection of enterovirus or other viral gene fragments in the endocardium, myocardium, pericardium, or pericardial effusion.
2. Impaired left ventricular systolic function (confirmed by non-invasive or invasive testing).
3. Elevated levels of CK, CK-MB, AST, or LDH early in the course of illness, with dynamic changes during the acute phase. If available, testing for cardiac troponin I or T, or myosin light or heavy chains may be performed.
(3) For those whose diagnosis remains unclear, long-term follow-up may be considered. When conditions permit, endomyocardial biopsy can be performed for viral gene detection and pathological examination.
When considering the diagnosis of viral myocarditis, it is necessary to exclude hyperthyroidism, mitral valve prolapse syndrome, and other diseases affecting the myocardium such as wind-dampness myocarditis, toxic myocarditis, coronary heart disease, connective tissue diseases, metabolic diseases, and Keshan disease (in Keshan disease-endemic areas). If conditions permit, any of the aforementioned etiological examinations must be performed.
bubble_chart Treatment Measures
A few viral infections such as measles and poliomyelitis can be prevented through vaccination.
The treatment of myocarditis targets two aspects: viral infection and myocardial inflammation.
For primary viral infections, recent studies suggest the use of interferon or interferon inducers for the prevention and treatment of myocarditis. Some Chinese herbal medicines, such as Isatis Root, Forsythia, Dyers Woad Leaf, and Giant Knotweed, have shown potential effectiveness against viral infections in preliminary experimental studies.
Patients with myocarditis should rest in bed and consume easily digestible foods rich in vitamins and proteins. Heart failure should be promptly controlled, but caution is required when using digitalis-like drugs, starting with small doses. Vasodilators and diuretics may also be used. Frequent premature beats or rapid arrhythmias should be treated with antiarrhythmic drugs. In cases of syncope or hypotension due to high-grade atrioventricular block, rapid ventricular rhythm, or sinoatrial node damage, electrical pacing or cardioversion may be necessary. Most patients with grade III atrioventricular block recover after passing the acute phase with the aid of a pacemaker.
The use of adrenal corticosteroids can improve heart failure in severe myocarditis and alleviate or eliminate severe arrhythmias (such as high-grade atrioventricular block). Their effect may be attributed to suppressing myocardial inflammation and edema, eliminating allergic reactions, and reducing toxin effects. However, experiments have shown that hormones inhibit interferon synthesis and release, accelerate viral proliferation, and worsen infections. Therefore, it is currently believed that general patients do not need to use them, especially within the first 10 days of onset. However, clinical practice has demonstrated that corticosteroids are still advisable for critically ill patients to help them through the critical period. For patients who respond poorly to other treatments or exhibit strong immune reactions, corticosteroids may also be considered within 10 days to one month after onset. For general myocarditis patients, immunosuppressive treatments such as corticosteroids and cyclosporine have not been proven beneficial.
Drugs that promote myocardial metabolism, such as adenosine triphosphate (ATP), coenzyme A, inosine, cyclic adenosine monophosphate (cAMP), and cytochrome C, may have auxiliary roles in treatment. Generally, 10–20 mg of ATP, 50 units of coenzyme A, 200–400 mg of inosine, 20–40 mg of cAMP, or 15 mg of cytochrome C can be administered intramuscularly 2–3 times daily. In recent years, coenzyme Q10 has also been used to treat myocarditis, with an oral dosage of 20–60 mg three times daily. For enhancing immune function, recent studies have found that Astragalus Root can improve immune function and cardiac performance, whether taken orally or injected. Other options include immunoribonucleic acid (6 mg injected subcutaneously weekly), thymosin (10 mg intramuscularly daily), or treatments such as transfer factor and interferon.
Most patients recover completely after appropriate treatment without any residual symptoms or signs. A very small number of patients die during the acute phase due to severe arrhythmias, acute heart failure, or cardiogenic shock. Some patients stabilize after several weeks or months but exhibit varying degrees of cardiac enlargement, reduced cardiac function, arrhythmias, or electrocardiographic changes. These conditions persist unchanged, likely due to myocardial scar formation after the acute phase, resulting in sequelae. Another subset of patients, due to persistent inflammation after the acute phase, develop chronic myocarditis, gradually presenting with progressive cardiac enlargement, declining cardiac function, and arrhythmias, ultimately succumbing to these complications after several years or even one or two decades. The exact timeframes for each stage are difficult to define, but generally, the acute phase lasts within 6 months, the convalescence stage spans 6 months to 1 year, and the chronic phase extends beyond 1 year. Chronic cases with an unclear acute phase can be difficult to distinguish from cardiomyopathy. Based on current understanding and available evidence, some cardiomyopathies evolve from myocarditis.
