Mycoplasma is a genus of bacteria that can

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1. 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

2. 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)

3. 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 as response is too sparse for this type to be labeled as
active myocarditis. Degeneration of myocytes is active myocarditis. Degeneration of myocytes is
not demonstrated by light microscopy. 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.

4. 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.

5. 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.

6. 
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.

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

8. 
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

9. 
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.

10. 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.

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

12. 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.

13. Initial symptoms in infants include the following:Initial symptoms in infants include the following:

IrritabilityIrritability
LethargyLethargy

Periodic episodes of pallorPeriodic episodes of pallor

FeverFever

14. 
HypothermiaHypothermia

TachypneaTachypnea

AnorexiaAnorexia

Failure to thriveFailure to thrive

15. 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 S
33 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.

16. 
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.

17. 
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 the Somnolence, hypotonia, and seizures can be associated if the
CNS is involved.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 may caused by direct viral damage and/or low cardiac output may
be present.be present.

18. 
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.

19. 
AdolescentsAdolescents

Presentation may be similar to that of younger children but Presentation may be similar to that of younger children but
with a more prominent decrease in exercise tolerance, lack with a more prominent decrease in exercise tolerance, lack
of energy, malaise, chest pain, low-grade fever, of energy, malaise, chest pain, low-grade fever,
arrhythmia, and cough.arrhythmia, and cough.

End-organ damage and low cardiac output may be present.End-organ damage and low cardiac output may be present.

20. CausesCauses
Infecting 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

21. 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

22. 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.

23. 
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

24. 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.

25. The late phase or second wave of T lymphocytes (CD4, The late phase or second wave of T lymphocytes (CD4,
CD8) begins approximately 1 week after the mouse has CD8) begins approximately 1 week after the mouse has
been inoculated with the virus. been inoculated with the virus.
T lymphocytes can injure cells in the following 3 ways: T lymphocytes can injure cells in the following 3 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

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

27. 
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.

28. 
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.

29. 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

30. 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

31. 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.

32. 
ECGECG

CXRCXR

EchocardiogramEchocardiogram

33. 
CBCCBC

PT , PTT , FDP , & D-diamersPT , PTT , FDP , & D-diamers

ABGABG

LFTLFT

34. 
Renal functionRenal function

Cardiac enzymesCardiac enzymes

Carnitine levelCarnitine level

35. 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

36. 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.

37. [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 than according to NYHA classification was obviously better than
that of the control group. that of the control group.
The creatine phosphokinase isoenzyme (CPK-MB), aspartate The creatine phosphokinase isoenzyme (CPK-MB), aspartate
transaminase (AST), lactate dehydrogenase (LDH) content transaminase (AST), lactate dehydrogenase (LDH) content
lowered in both groups, but more significantly lowered in the lowered in both groups, but more significantly lowered in the
treated group than in the control group (P < 0.05, P < 0.01).treated group than in the 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).

38. 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.

39. 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.

40. 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.

42. 
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.