VIRAL MYOCARDITIS VIRAL MYOCARDITIS AN UPDATEAN UPDATE

BYBY

JAMEEL A. ALATA, MD.JAMEEL A. ALATA, MD.

CONSULTANT & ASSISTANT CONSULTANT & ASSISTANT PROFESSOR OF PEDIATRICS & PROFESSOR OF PEDIATRICS &

PEDIATRIC CARDIOLOGYPEDIATRIC CARDIOLOGY

INTRODUCTIONINTRODUCTION

Myocarditis is an inflammatory disorder of the Myocarditis is an inflammatory disorder of the myocardium with necrosis of the myocytes and myocardium with necrosis of the myocytes and associated inflammatory infiltrate. It is usually associated inflammatory infiltrate. It is usually caused by a viral infection, particularly adenovirus caused by a viral infection, particularly adenovirus and enterovirus infections (eg, coxsackievirus)and enterovirus infections (eg, coxsackievirus)

suspected myocarditis can be classified into the suspected myocarditis can be classified into the following 3 types based on pathologic findings as following 3 types based on pathologic findings as defined in the Dallas Criteria (1987)defined in the Dallas Criteria (1987)

1.1. Active myocarditis is characterized by abundant Active myocarditis is characterized by abundant inflammatory cells and myocardial necrosis. inflammatory cells and myocardial necrosis.

2.2. Borderline myocarditis is characterized by an Borderline myocarditis is characterized by an inflammatory response, but the inflammatory inflammatory response, but the inflammatory response is too sparse for this type to be labeled response is too sparse for this type to be labeled as active myocarditis. Degeneration of myocytes as active myocarditis. Degeneration of myocytes is not demonstrated by light microscopy. is not demonstrated by light microscopy.

3.3. NonmyocarditisNonmyocarditis

If an active or borderline inflammatory process is If an active or borderline inflammatory process is found, follow-up biopsies can be subclassified found, follow-up biopsies can be subclassified into ongoing, resolving, or resolved myocarditis.into ongoing, resolving, or resolved myocarditis.

PathophysiologyPathophysiology

Myocarditis generally results in a decrease in Myocarditis generally results in a decrease in myocardial function, with concomitant myocardial function, with concomitant enlargement of the heart and an increase in the enlargement of the heart and an increase in the end-diastolic volume caused by increased preload. end-diastolic volume caused by increased preload.

The progressive increase in The progressive increase in left ventricular end-left ventricular end-diastolic volume increases left atrial, pulmonary diastolic volume increases left atrial, pulmonary venous, and arterial pressuresvenous, and arterial pressures, resulting in , resulting in increasing hydrostatic forces. These increased increasing hydrostatic forces. These increased forces lead to both pulmonary edema and forces lead to both pulmonary edema and congestive heart failure. congestive heart failure.

FrequencyFrequency

The World Health Organization reports that The World Health Organization reports that incidence of cardiovascular involvement incidence of cardiovascular involvement after enteroviral infection is 1-4%, after enteroviral infection is 1-4%,

Incidence varies greatly among countries Incidence varies greatly among countries and is related to hygiene and socioeconomic and is related to hygiene and socioeconomic conditions. Availability of medical services conditions. Availability of medical services and immunizations also affect incidence.and immunizations also affect incidence.

Occasional epidemics of viral infections Occasional epidemics of viral infections have been reported with an associated have been reported with an associated higher incidence of myocarditis. higher incidence of myocarditis.

Enteroviruses, such as coxsackievirus and Enteroviruses, such as coxsackievirus and echovirus, and adenoviruses, particularly echovirus, and adenoviruses, particularly types 2 and 5, are the most commonly types 2 and 5, are the most commonly involved organisms. involved organisms.

Mortality/MorbidityMortality/Morbidity With suspected coxsackievirus B, the mortality rate With suspected coxsackievirus B, the mortality rate

is higher in newborns (75%) than in older infants is higher in newborns (75%) than in older infants and children (10-25%). and children (10-25%).

Complete recovery of ventricular function has been Complete recovery of ventricular function has been reported in as many as 50% of patients. reported in as many as 50% of patients.

Some patients develop chronic myocarditis Some patients develop chronic myocarditis (ongoing or resolving) and/or dilated (ongoing or resolving) and/or dilated cardiomyopathy and may eventually require cardiac cardiomyopathy and may eventually require cardiac transplantation. transplantation.

No racial predilection exists. No racial predilection exists.

No sex predilection exists in humans, but No sex predilection exists in humans, but there is some indication in laboratory animals there is some indication in laboratory animals that the disease may be more aggressive in that the disease may be more aggressive in males than in females.males than in females.

Certain strains of female mice had a reduced Certain strains of female mice had a reduced inflammatory process when treated with inflammatory process when treated with estradiol.estradiol.

Epidemiology

In other studies, testosterone appeared to increase In other studies, testosterone appeared to increase cytolytic activity of T lymphocytes in male mice.cytolytic activity of T lymphocytes in male mice.

No age predilection exists.No age predilection exists.

Younger patients, especially newborns and Younger patients, especially newborns and infants, and immunocompromised patients may be infants, and immunocompromised patients may be more susceptible to myocarditis.more susceptible to myocarditis.

CLINICAL CLINICAL

Heart failure: This is the most common Heart failure: This is the most common presenting picture in all ages.presenting picture in all ages.

Chest pain: Although rare in young Chest pain: Although rare in young children, this may be the initial presentation children, this may be the initial presentation for older children, adolescents, and adults. for older children, adolescents, and adults.

Chest pain may be due to myocardial Chest pain may be due to myocardial ischemia or concurrent pericarditis.ischemia or concurrent pericarditis.

Arrhythmia: Arrhythmia: Patients can present with any type of dysrhythmia, including ;Patients can present with any type of dysrhythmia, including ;

1 ) Atrioventricular conduction disturbances. 1 ) Atrioventricular conduction disturbances.

2 ) Sinus tachycardia is typical and the rate is faster than 2 ) Sinus tachycardia is typical and the rate is faster than expected for the degree of fever present, which is typically expected for the degree of fever present, which is typically low-grade. low-grade.

3 )Junctional tachycardia is also seen and can be difficult to 3 )Junctional tachycardia is also seen and can be difficult to control medically.control medically.

Dilated cardiomyopathy:Dilated cardiomyopathy:

There is still debate over whether There is still debate over whether myocarditis progresses to dilated myocarditis progresses to dilated cardiomyopathy. cardiomyopathy.

Many investigators believe that dilated Many investigators believe that dilated cardiomyopathy is a direct result of a cardiomyopathy is a direct result of a previously burned-out myocarditis episode.previously burned-out myocarditis episode.

Initial symptoms in infants include the Initial symptoms in infants include the following:following:

IrritabilityIrritability

LethargyLethargy

Periodic episodes of pallorPeriodic episodes of pallor

FeverFever

HypothermiaHypothermia

TachypneaTachypnea

AnorexiaAnorexia

Failure to thriveFailure to thrive

Physical EXAMPhysical EXAM

Tachycardia, weak pulse, cool extremities, Tachycardia, weak pulse, cool extremities, decreased capillary refill, and pale or decreased capillary refill, and pale or mottled skin may be present.mottled skin may be present.

Heart sounds may be muffled, especially in Heart sounds may be muffled, especially in the presence of pericarditis. An Sthe presence of pericarditis. An S33 may be may be present, and a heart murmur caused by present, and a heart murmur caused by atrioventricular valve regurgitation may be atrioventricular valve regurgitation may be heard.heard.

Hepatomegaly may be present in younger Hepatomegaly may be present in younger children. children.

Rales may be heard in older children.Rales may be heard in older children.

Jugular venous distention and edema of the Jugular venous distention and edema of the lower extremities may be present.lower extremities may be present.

NeonatesNeonates

Neonates may seem irritable, be in respiratory distress, and Neonates may seem irritable, be in respiratory distress, and exhibit signs of sepsis.exhibit signs of sepsis.

Somnolence, hypotonia, and seizures can be associated if Somnolence, hypotonia, and seizures can be associated if the CNS is involved.the CNS is involved.

Hypothermia or hyperthermia, oliguria, elevated liver Hypothermia or hyperthermia, oliguria, elevated liver enzymes and elevated blood urea nitrogen and creatinine enzymes and elevated blood urea nitrogen and creatinine caused by direct viral damage and/or low cardiac output caused by direct viral damage and/or low cardiac output may be present.may be present.

InfantsInfants

Signs include failure to thrive, anorexia, tachypnea, tachycardia, Signs include failure to thrive, anorexia, tachypnea, tachycardia, wheezing, and diaphoresis with feeding.wheezing, and diaphoresis with feeding.

In severe cases, low cardiac output may progress to acidosis and In severe cases, low cardiac output may progress to acidosis and death.death.

End organ damage may occur because of direct viral infestation or End organ damage may occur because of direct viral infestation or because of low cardiac output.because of low cardiac output.

CNS involvement may also occur.CNS involvement may also occur.

AdolescentsAdolescents

Presentation may be similar to that of younger children Presentation may be similar to that of younger children but with a more prominent decrease in exercise but with a more prominent decrease in exercise tolerance, lack of energy, malaise, chest pain, low-grade tolerance, lack of energy, malaise, chest pain, low-grade fever, arrhythmia, and cough.fever, arrhythmia, and cough.

End-organ damage and low cardiac output may be End-organ damage and low cardiac output may be present.present.

CausesCausesInfecting organisms include the following:Infecting organisms include the following:

Coxsackievirus types A and B, especially type B, are the Coxsackievirus types A and B, especially type B, are the most common viral causes of myocarditis.most common viral causes of myocarditis.

Adenovirus (types 2 and 5 most common) Adenovirus (types 2 and 5 most common)

Cytomegalovirus Cytomegalovirus EchovirusEchovirus Epstein-Barr virus Epstein-Barr virus Hepatitis C virus Hepatitis C virus

Herpes virus Herpes virus Human immunodeficiency virusHuman immunodeficiency virus Influenza and parainfluenzaInfluenza and parainfluenza Measles Measles Mumps, associated with endocardial fibroelastosis Mumps, associated with endocardial fibroelastosis

(EFE) (EFE) Parvovirus B19Parvovirus B19 Poliomyelitis virusPoliomyelitis virus RubellaRubella VaricellaVaricella

Murine modelMurine model

The coxsackievirus and adenovirus receptor acts The coxsackievirus and adenovirus receptor acts as the receptor for the four most common viruses as the receptor for the four most common viruses causing human myocarditis: causing human myocarditis:

Type C (type 2 and type 5) adenovirus Type C (type 2 and type 5) adenovirus andand Coxsackievirus B3 and B4.Coxsackievirus B3 and B4.

Coxsackievirus B serotypes 1-6 have been Coxsackievirus B serotypes 1-6 have been associated with human myocarditis, but the most associated with human myocarditis, but the most serious cases have been attributed to types 3 and 4.serious cases have been attributed to types 3 and 4.

The primary response to the early phase of The primary response to the early phase of viral infection is the release of natural killer viral infection is the release of natural killer (NK) cells, which lyse infected myocytes. (NK) cells, which lyse infected myocytes. This helps clear the virus from the system.This helps clear the virus from the system.

PATHOPHYSIOLOGY

NK cells also induce expression of major NK cells also induce expression of major histocompatibility complex antigens on histocompatibility complex antigens on myocytes by releasing cytokines, which myocytes by releasing cytokines, which prepare the NK cells to interact with T prepare the NK cells to interact with T lymphocytes. lymphocytes.

Animal models depleted of NK cells Animal models depleted of NK cells develop a more severe form of myocarditis.develop a more severe form of myocarditis.

The late phase or second wave of T lymphocytes The late phase or second wave of T lymphocytes (CD4, CD8) begins approximately 1 week after the (CD4, CD8) begins approximately 1 week after the mouse has been inoculated with the virus. mouse has been inoculated with the virus.

T lymphocytes can injure cells in the following 3 T lymphocytes can injure cells in the following 3 ways: ways:

Stimulation of cytotoxic T cells Stimulation of cytotoxic T cells

Production of antibody and antibody-dependent Production of antibody and antibody-dependent myotoxicity myotoxicity

Direct antibody and complement formationDirect antibody and complement formation

These ongoing processes are considered genetically These ongoing processes are considered genetically mediated autoimmune processes.mediated autoimmune processes.

Two different strains of cytolytic T cells have been Two different strains of cytolytic T cells have been recognized; one strain attacks virus-infected recognized; one strain attacks virus-infected myocytes and the other strain attacks uninfected myocytes and the other strain attacks uninfected cells.cells.

Enzymatic cleavage by viral proteins of Enzymatic cleavage by viral proteins of cytoskeletal proteins appears to play a role in cytoskeletal proteins appears to play a role in development of dilated cardiomyopathy.development of dilated cardiomyopathy.

Apoptosis appears to play a role also in the Apoptosis appears to play a role also in the development of dilated cardiomyopathy.development of dilated cardiomyopathy.

Various kinds of autoantibodies have been found Various kinds of autoantibodies have been found in as many as 60% of patients with myocarditis. in as many as 60% of patients with myocarditis.

These includeThese include

complement-fixing antimyolemmal antibodies,complement-fixing antimyolemmal antibodies,

complement-fixing antisarcolemmal antibodies,complement-fixing antisarcolemmal antibodies, antimyosin heavy chain antibodies, and antimyosin heavy chain antibodies, and

anti–alpha myosin antibodies.anti–alpha myosin antibodies. Although their role in the disease is not completely understood, their Although their role in the disease is not completely understood, their

presence may serve as apresence may serve as a marker marker for diagnosing myocarditis in the for diagnosing myocarditis in the future.future.

DIFFERENTIALSDIFFERENTIALS

Anomalous Left Coronary Artery from the Pulmonary Anomalous Left Coronary Artery from the Pulmonary Artery.Artery.

Aortic Aortic StenosisStenosis,, Valvar Valvar

Cardiac Tumors Cardiac Tumors

CardiomyopathyCardiomyopathy, Dilated , Dilated

CarnitineCarnitine Deficiency Deficiency

CoarctationCoarctation of the Aorta of the Aorta

Coronary Artery Anomalies Coronary Artery Anomalies

Endocardial Fibroelastosis Endocardial Fibroelastosis

EnteroviralEnteroviral Infections Infections

Glycogen Storage Disease Type I Glycogen Storage Disease Type I

Glycogen Storage Disease Type II Glycogen Storage Disease Type II

MyocarditisMyocarditis,, Nonviral Nonviral

PericarditisPericarditis, Viral , Viral

InvestigationsInvestigations

Virus identification ;Virus identification ;

1 ) Cultures from blood , stools and throat.1 ) Cultures from blood , stools and throat.

2 ) Acute & convalescent sera.2 ) Acute & convalescent sera.

ECGECG

CXRCXR

EchocardiogramEchocardiogram

CBCCBC

PT , PTT , FDP , & D-diamersPT , PTT , FDP , & D-diamers

ABGABG

LFTLFT

Renal functionRenal function

Cardiac enzymesCardiac enzymes

Carnitine levelCarnitine level

TreatmentTreatment

Bedrest or limitation of activity in the acute phase.Bedrest or limitation of activity in the acute phase.

Intubation & ventilation.Intubation & ventilation.

Treatment of PHTNTreatment of PHTN

Diuretics.Diuretics.

InotropesInotropes

Digoxin ( better no loading & later on in the Digoxin ( better no loading & later on in the course of the disease ).course of the disease ).

High dose IVIG.High dose IVIG.

ACE inhibitors.ACE inhibitors.

Corticosteroids ?Corticosteroids ?

Sedation and paralysis.Sedation and paralysis.

[Clinical study on therapeutic effects of treatment [Clinical study on therapeutic effects of treatment according to syndrome differentiation of according to syndrome differentiation of

traditional Chinese medicine combined with traditional Chinese medicine combined with captopril on severe viral myocarditis complicated captopril on severe viral myocarditis complicated

heart failure]( CHINESE )heart failure]( CHINESE )

RESULTS: The therapeutic effect of the treated group RESULTS: The therapeutic effect of the treated group according to NYHA classification was obviously better according to NYHA classification was obviously better than that of the control group. than that of the control group.

The creatine phosphokinase isoenzyme (CPK-MB), The creatine phosphokinase isoenzyme (CPK-MB), aspartate transaminase (AST), lactate dehydrogenase aspartate transaminase (AST), lactate dehydrogenase (LDH) content lowered in both groups, but more (LDH) content lowered in both groups, but more significantly lowered in the treated group than in the significantly lowered in the treated group than in the control group (P < 0.05, P < 0.01).control group (P < 0.05, P < 0.01).

The improvement of S-T segment of ECG in the treated The improvement of S-T segment of ECG in the treated group was better than that in the control (P < 0.01); also group was better than that in the control (P < 0.01); also some parameters of heart function and motorial toleration some parameters of heart function and motorial toleration were bettered in the treated group more significantly (P < were bettered in the treated group more significantly (P < 0.01).0.01).

Carvedilol increases the production of Carvedilol increases the production of interleukin-12 and interferon-gamma and interleukin-12 and interferon-gamma and

improves the survival of mice infected with the improves the survival of mice infected with the encephalomyocarditis virus.encephalomyocarditis virus.

( JAPAN )( JAPAN ) RESULTS:RESULTS: Carvedilol Carvedilol 1)Improved the 14-day survival of the animals.1)Improved the 14-day survival of the animals.2)Attenuated myocardial lesions on day 7, and 2)Attenuated myocardial lesions on day 7, and 3 )Increased myocardial levels of interleukin (IL)-12 and 3 )Increased myocardial levels of interleukin (IL)-12 and

interferon (IFN)-gamma, whereas reducing myocardial virus interferon (IFN)-gamma, whereas reducing myocardial virus replication.replication.

Propranolol Propranolol also attenuated myocardial lesions, but to a lesser also attenuated myocardial lesions, but to a lesser extent, and increased IL-12 and IFN-gamma levels. extent, and increased IL-12 and IFN-gamma levels.

MetoprololMetoprolol had no effect in this model. Encephalomyocarditis had no effect in this model. Encephalomyocarditis virus infection increased plasma catecholamine levels.virus infection increased plasma catecholamine levels.

Successful treatment of Successful treatment of enterovirus-induced myocarditis enterovirus-induced myocarditis with interferon-alpha.( ITALY ).with interferon-alpha.( ITALY ).

Non- randomized, placebo-controlled studies Non- randomized, placebo-controlled studies have investigated interferon-alpha therapy in have investigated interferon-alpha therapy in enterovirus-proven myocarditis. enterovirus-proven myocarditis.

This report describes 2 patients with This report describes 2 patients with enterovirus-induced myocarditis (1 with enterovirus-induced myocarditis (1 with associated Churg-Strauss syndrome) who at associated Churg-Strauss syndrome) who at follow-up endomyocardial biopsy showed follow-up endomyocardial biopsy showed clinical and hemodynamic improvement and clinical and hemodynamic improvement and viral clearance (using polymerase chain viral clearance (using polymerase chain reaction) after interferon-alpha therapy.reaction) after interferon-alpha therapy.

Cardiac MRI in suspected Cardiac MRI in suspected myocarditismyocarditis ( GERMANY ) ( GERMANY )

Acute myocarditis was diagnosed in 9 patients and Acute myocarditis was diagnosed in 9 patients and cardiac sarcoidosis in 2 patients. Late enhancement was cardiac sarcoidosis in 2 patients. Late enhancement was observed in 4 patients with acute myocarditis and in observed in 4 patients with acute myocarditis and in both patients with cardiac sarcoidosis. both patients with cardiac sarcoidosis.

Semiquantitative evaluation revealed 9 true positive, 9 Semiquantitative evaluation revealed 9 true positive, 9 true negative, 1 false positive and 2 false negative true negative, 1 false positive and 2 false negative results. results.

CONCLUSION: Cardiac MRI has the potential to detect acute CONCLUSION: Cardiac MRI has the potential to detect acute myocarditis and to diagnose cardiac sarcoidosis. Late myocarditis and to diagnose cardiac sarcoidosis. Late enhancement of Gd-DTPA can be found in both viral enhancement of Gd-DTPA can be found in both viral myocarditis and cardiac sarcoidosis.myocarditis and cardiac sarcoidosis.

Here we show the essential role of Janus kinase Here we show the essential role of Janus kinase (JAK) signaling in cardiac myocyte antiviral (JAK) signaling in cardiac myocyte antiviral defense and a negative role of an intrinsic JAK defense and a negative role of an intrinsic JAK inhibitor, the suppressor of cytokine signaling inhibitor, the suppressor of cytokine signaling (SOCS), in the early disease process. ( USA ) (SOCS), in the early disease process. ( USA )

strategies directed at inhibition of SOCS in the strategies directed at inhibition of SOCS in the heart and perhaps other organs can augment the heart and perhaps other organs can augment the host-cell antiviral system, thus preventing viral-host-cell antiviral system, thus preventing viral-mediated end-organ damage during the early mediated end-organ damage during the early stages of infection.stages of infection.