VIRAL MYOCARDITIS AN UPDATE

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VIRAL MYOCARDITIS AN UPDATE

• BY
• JAMEEL A. ALATA, MD.
• CONSULTANT ASSISTANT PROFESSOR OF PEDIATRICS
  PEDIATRIC CARDIOLOGY

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INTRODUCTION

• Myocarditis is an inflammatory disorder of the
  myocardium with necrosis of the myocytes and
  associated inflammatory infiltrate. It is usually
  caused by a viral infection, particularly
  adenovirus and enterovirus infections (eg,
  coxsackievirus)
• suspected myocarditis can be classified into the
  following 3 types based on pathologic findings as
  defined in the Dallas Criteria (1987)

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• Active myocarditis is characterized by abundant
  inflammatory cells and myocardial necrosis.
• Borderline myocarditis is characterized by an
  inflammatory response, but the inflammatory
  response is too sparse for this type to be
  labeled as active myocarditis. Degeneration of
  myocytes is not demonstrated by light microscopy.
  
• Nonmyocarditis
• If an active or borderline inflammatory process
  is found, follow-up biopsies can be subclassified
  into ongoing, resolving, or resolved myocarditis.

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Pathophysiology

• Myocarditis generally results in a decrease in
  myocardial function, with concomitant enlargement
  of the heart and an increase in the end-diastolic
  volume caused by increased preload.
• The progressive increase in left ventricular
  end-diastolic volume increases left atrial,
  pulmonary venous, and arterial pressures,
  resulting in increasing hydrostatic forces. These
  increased forces lead to both pulmonary edema and
  congestive heart failure.

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Frequency

• The World Health Organization reports that
  incidence of cardiovascular involvement after
  enteroviral infection is 1-4,
• Incidence varies greatly among countries and is
  related to hygiene and socioeconomic conditions.
  Availability of medical services and
  immunizations also affect incidence.

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• Occasional epidemics of viral infections have
  been reported with an associated higher incidence
  of myocarditis.
• Enteroviruses, such as coxsackievirus and
  echovirus, and adenoviruses, particularly types 2
  and 5, are the most commonly involved organisms.

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Mortality/Morbidity

• With suspected coxsackievirus B, the mortality
  rate is higher in newborns (75) than in older
  infants and children (10-25).
• Complete recovery of ventricular function has
  been reported in as many as 50 of patients.
• Some patients develop chronic myocarditis
  (ongoing or resolving) and/or dilated
  cardiomyopathy and may eventually require cardiac
  transplantation.

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Epidemiology

• No racial predilection exists.
• No sex predilection exists in humans, but there
  is some indication in laboratory animals that the
  disease may be more aggressive in males than in
  females.
• Certain strains of female mice had a reduced
  inflammatory process when treated with estradiol.

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• In other studies, testosterone appeared to
  increase cytolytic activity of T lymphocytes in
  male mice.
• No age predilection exists.
• Younger patients, especially newborns and
  infants, and immunocompromised patients may be
  more susceptible to myocarditis.

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CLINICAL

• Heart failure This is the most common presenting
  picture in all ages.
• Chest pain Although rare in young children, this
  may be the initial presentation for older
  children, adolescents, and adults.
• Chest pain may be due to myocardial ischemia or
  concurrent pericarditis.

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• Arrhythmia
• Patients can present with any type of
  dysrhythmia, including
• 1 ) Atrioventricular conduction disturbances.
• 2 ) Sinus tachycardia is typical and the rate is
  faster than expected for the degree of fever
  present, which is typically low-grade.
• 3 )Junctional tachycardia is also seen and can be
  difficult to control medically.

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• Dilated cardiomyopathy
• There is still debate over whether myocarditis
  progresses to dilated cardiomyopathy.
• Many investigators believe that dilated
  cardiomyopathy is a direct result of a previously
  burned-out myocarditis episode.

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• Initial symptoms in infants include the
  following
• Irritability
• Lethargy
• Periodic episodes of pallor
• Fever

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• Hypothermia
• Tachypnea
• Anorexia
• Failure to thrive

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Physical EXAM

• Tachycardia, weak pulse, cool extremities,
  decreased capillary refill, and pale or mottled
  skin may be present.
• Heart sounds may be muffled, especially in the
  presence of pericarditis. An S3 may be present,
  and a heart murmur caused by atrioventricular
  valve regurgitation may be heard.

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• Hepatomegaly may be present in younger children.
• Rales may be heard in older children.
• Jugular venous distention and edema of the lower
  extremities may be present.

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• Neonates
• Neonates may seem irritable, be in respiratory
  distress, and exhibit signs of sepsis.
• Somnolence, hypotonia, and seizures can be
  associated if the CNS is involved.
• Hypothermia or hyperthermia, oliguria, elevated
  liver enzymes and elevated blood urea nitrogen
  and creatinine caused by direct viral damage
  and/or low cardiac output may be present.

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• Infants
• Signs include failure to thrive, anorexia,
  tachypnea, tachycardia, wheezing, and diaphoresis
  with feeding.
• In severe cases, low cardiac output may progress
  to acidosis and death.
• End organ damage may occur because of direct
  viral infestation or because of low cardiac
  output.
• CNS involvement may also occur.

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

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Causes

• Infecting organisms include the following
• Coxsackievirus types A and B, especially type B,
  are the most common viral causes of myocarditis.
• Adenovirus (types 2 and 5 most common)
• Cytomegalovirus
• Echovirus
• Epstein-Barr virus
• Hepatitis C virus

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• Herpes virus
• Human immunodeficiency virus
• Influenza and parainfluenza
• Measles
• Mumps, associated with endocardial fibroelastosis
  (EFE)
• Parvovirus B19
• Poliomyelitis virus
• Rubella
• Varicella

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Murine model

• The coxsackievirus and adenovirus receptor acts
  as the receptor for the four most common viruses
  causing human myocarditis
• Type C (type 2 and type 5) adenovirus and
• Coxsackievirus B3 and B4.
• Coxsackievirus B serotypes 1-6 have been
  associated with human myocarditis, but the most
  serious cases have been attributed to types 3 and
  4.

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PATHOPHYSIOLOGY

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

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• NK cells also induce expression of major
  histocompatibility complex antigens on myocytes
  by releasing cytokines, which prepare the NK
  cells to interact with T lymphocytes.
• Animal models depleted of NK cells develop a more
  severe form of myocarditis.

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• The late phase or second wave of T lymphocytes
  (CD4, CD8) begins approximately 1 week after the
  mouse has been inoculated with the virus.
• T lymphocytes can injure cells in the
  following 3 ways
• Stimulation of cytotoxic T cells
• Production of antibody and antibody-dependent
  myotoxicity
• Direct antibody and complement formation

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• These ongoing processes are considered
  genetically mediated autoimmune processes.
• Two different strains of cytolytic T cells have
  been recognized one strain attacks
  virus-infected myocytes and the other strain
  attacks uninfected cells.
• Enzymatic cleavage by viral proteins of
  cytoskeletal proteins appears to play a role in
  development of dilated cardiomyopathy.

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• Apoptosis appears to play a role also in the
  development of dilated cardiomyopathy.
• Various kinds of autoantibodies have been found
  in as many as 60 of patients with myocarditis.

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• These include
• complement-fixing antimyolemmal antibodies,
• complement-fixing antisarcolemmal antibodies,
• antimyosin heavy chain antibodies, and
• antialpha myosin antibodies.
• Although their role in the disease is not
  completely understood, their presence may serve
  as a marker for diagnosing myocarditis in the
  future.

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DIFFERENTIALS

• Anomalous Left Coronary Artery from the Pulmonary
  Artery.
• Aortic Stenosis, Valvar
• Cardiac Tumors
• Cardiomyopathy, Dilated
• Carnitine Deficiency
• Coarctation of the Aorta

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• Coronary Artery Anomalies
• Endocardial Fibroelastosis
• Enteroviral Infections
• Glycogen Storage Disease Type I
• Glycogen Storage Disease Type II
• Myocarditis, Nonviral
• Pericarditis, Viral

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Investigations

• Virus identification
• 1 ) Cultures from blood , stools and throat.
• 2 ) Acute convalescent sera.

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• ECG
• CXR
• Echocardiogram

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• CBC
• PT , PTT , FDP , D-diamers
• ABG
• LFT

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• Renal function
• Cardiac enzymes
• Carnitine level

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Treatment

• Bedrest or limitation of activity in the acute
  phase.
• Intubation ventilation.
• Treatment of PHTN
• Diuretics.
• Inotropes

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• Digoxin ( better no loading later on in the
  course of the disease ).
• High dose IVIG.
• ACE inhibitors.
• Corticosteroids ?
• Sedation and paralysis.

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Clinical study on therapeutic effects of
treatment according to syndrome differentiation
of traditional Chinese medicine combined with
captopril on severe viral myocarditis complicated
heart failure( CHINESE )

• RESULTS The therapeutic effect of the treated
  group according to NYHA classification was
  obviously better than that of the control group.
• The creatine phosphokinase isoenzyme (CPK-MB),
  aspartate transaminase (AST), lactate
  dehydrogenase (LDH) content lowered in both
  groups, but more significantly lowered in the
  treated group than in the control group (P lt
  0.05, P lt 0.01).
• The improvement of S-T segment of ECG in the
  treated group was better than that in the control
  (P lt 0.01) also some parameters of heart
  function and motorial toleration were bettered in
  the treated group more significantly (P lt 0.01).

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Carvedilol increases the production of
interleukin-12 and interferon-gamma and improves
the survival of mice infected with the
encephalomyocarditis virus.( JAPAN )

• RESULTS
• Carvedilol
• 1)Improved the 14-day survival of the animals.
• 2)Attenuated myocardial lesions on day 7, and
• 3 )Increased myocardial levels of interleukin
  (IL)-12 and interferon (IFN)-gamma, whereas
  reducing myocardial virus replication.
• Propranolol also attenuated myocardial lesions,
  but to a lesser extent, and increased IL-12 and
  IFN-gamma levels.
• Metoprolol had no effect in this model.
  Encephalomyocarditis virus infection increased
  plasma catecholamine levels.

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

• Non- randomized, placebo-controlled studies have
  investigated interferon-alpha therapy in
  enterovirus-proven myocarditis.
• This report describes 2 patients with
  enterovirus-induced myocarditis (1 with
  associated Churg-Strauss syndrome) who at
  follow-up endomyocardial biopsy showed clinical
  and hemodynamic improvement and viral clearance
  (using polymerase chain reaction) after
  interferon-alpha therapy.

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Cardiac MRI in suspected myocarditis ( GERMANY )

• Acute myocarditis was diagnosed in 9 patients and
  cardiac sarcoidosis in 2 patients. Late
  enhancement was observed in 4 patients with acute
  myocarditis and in both patients with cardiac
  sarcoidosis.
• Semiquantitative evaluation revealed 9 true
  positive, 9 true negative, 1 false positive and 2
  false negative results.
• CONCLUSION Cardiac MRI has the potential to
  detect acute myocarditis and to diagnose cardiac
  sarcoidosis. Late enhancement of Gd-DTPA can be
  found in both viral myocarditis and cardiac
  sarcoidosis.

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THANK YOU
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• Here we show the essential role of Janus kinase
  (JAK) signaling in cardiac myocyte antiviral
  defense and a negative role of an intrinsic JAK
  inhibitor, the suppressor of cytokine signaling
  (SOCS), in the early disease process. ( USA )
• strategies directed at inhibition of SOCS in the
  heart and perhaps other organs can augment the
  host-cell antiviral system, thus preventing
  viral-mediated end-organ damage during the early
  stages of infection.