Seminar on Acute myocarditis for Medical professionals and students

1. SEMINAR 17/07/2013
DR PAWAN KUMAR OLA

3.  Acute myocarditis is an inflammatory disease of
the heart muscle that may progress to dilated
cardiomyopathy and chronic heart failure.
 Myocarditis may present with a wide range of
symptoms, ranging from mild dyspnea or chest
pain that resolves without specific therapy to
cardiogenic shock and death.
 DCM with chronic heart failure is the major long-
term sequela of myocarditis.

4.  According to WHO/ISFC myocarditis is an
inflammatory disease of the myocardium,diagnosed
by established histological,immunological and
immunohistochemical criteria.
 Three distinct forms of inflammatory cardiomyopathy
(myocarditis associated with cardiac dysfunction) are
recognised:idiopathic,autoimmune and infectious.
 Various infectious agents may cause myocarditis but
most common are the viral agents.
Circulation 1996;93:341-2

5.  Classic Dallas criteria for the pathologic diagnosis of
myocarditis require the presence of inflammatory
cells simultaneous with evidence of myocyte necrosis
on the same microscopic section.
 Borderline myocarditis is characterized by
inflammatory cell infiltrate without myocardial
necrosis.
Am J Cardiovasc Pathol 1:3,1987

6. H&E stain Acute myocarditis showing inflammatory cells
with myocyte damage

7.  Dallas criteria are limited by variability in
interpretation, lack of prognostic value and low
sensitivity.
 Alternative pathological classification based on cell-
specific immunoperoxidase stains for surface
antigen;anti-CD3,anti-CD4,anti-CD20,anti-CD68
anti-HLA.
 Criteria based on immunoperoxidase staining have
greater sensitivity and may have prognostic value.
Kindermann I et al,Circulation 2008;118:639-48.
Herskowitz et al, JACC 1990;15:624-32

8. CD3 immunostaining of T lymphocytes in acute
myocarditis
Herskowitz et al, JACC 1990;15:624-32

9.  The precise incidence of myocarditis is difficult
to ascertain.
 Recent pathologic series examining young adults
who had suffered sudden death suggested an
incidence of myocarditis around 8.6%.
Fabre A,Sheppard MN:Heart 92:316,2006
 When patients with idiopathic dilated
cardiomyopathy only are considered then
myocarditis accounts for 10-40%.
Nugent et al, NEJM 348:1639,2003

11.  Viruses are the most common agents.
 The spectrum of viruses shifted from
coxsackievirus B to adenovirus in the late 1990s.
 Enterovirus (1980s) →Adenovirus (1990s) →
parvovirus B19 and human herpesvirus 6
 Adenoviral infections can be much more virulent
than coxsackievirus and can cause extensive cell
death without comparable inflammatory
response.
Kuhl U et al, Circulation 2005;112:1965-70
Mahrholdt H et al, Circulation 2006;114:1581-90

12.  Bowles & coworkers analyzed biopsy specimens from
624 patients with PCR and found overall viral
positivity was 38% (239/624).
 On analysis,22.8% tested positive for adenovirus,
13.6% for enterovirus and 1% for parvovirus.
Bowles et al, JACC 42:466,2003

13.  Hepatitis C virus agent mainly seen in Asian countries
such as Japan (Hepatitis C infection is also overall
more prevalent in Asia).
 Many of the patients with Hepatitis C myocarditis
exhibit a hypertrophic cardiomyopathy phenotype
rather than a dilated heart.

14.  Dobutamine may be associated with Eosinophilic myocarditis
as a hypersensitivity reaction.

16. Pathogenesis of myocarditis-
 Phase 1- cardiac injury and activation of the innate
immune response.
 Phase 2- acute myocarditis (acquired immune
response)
 Phase 3- recovery or persistent cardiomyopathy.
N Engl J Med 2009;360:1526-38

17.  Prog Cardiovasc Dis 2010;52:274-288

18.  Viruses enter cardiac myocytes or macrophages
through specific receptors and coreceptors.
 Receptor for coxsackievirus B and adenovirus 2 &5 is
the Human Coxsackie Adenovirus Receptor (CAR).
 The virulence of coxsackievirus B is also modified by
variations in its viral genome as well as in host
factors such as selenium deficiency and mercury
exposure.

19. Innate immune response
determines the acquired T
and B cell response.
CD4+T lymphocytes are
key mediators of cardiac
damage in autoimmune
myocarditis.
Circulating CD4+T cells
are under the control of
Regulatory T cells (T reg).
N Engl J Med 2009;360:1526-38

20.  Cardiac injury activates the innate
immune mechanisms like TLR2 &
TLR4.
 They induce proinflammatory
cytokines like TNF and IL-1β.
 They directly alter cardiac function
and promote extracellular matrix
remodelling,resulting in fibrosis and
cardiac dilation.
 TLR3 & TLR9 reduce acute
myocarditis while TLR2 & TLR4
which increase viral replication and
immune response to
infection,increase disease.
Heart 2012;98:835-840

22.  Clinical presentation can range from asymptomatic
ECG or ECHO findings to cardiac dysfunction,
arrhythmias or heart failure and hemodynamic
collapse.
 Myocarditis typically has a bimodal distribution in
terms of age in the population.
 Acute presentation is common in young children. In
contrast,the presenting symptoms are more subtle
and insidious,often with DCM and heart failure,in
the older adult population.

23.  Acute myocarditis
 Fulminant myocarditis
 Giant cell myocarditis
 Chronic active myocarditis
 Eosinophilic myocarditis
 Peripartum cardiomyopathy

24.  The viral prodrome of fever, chills, myalgia and
constitutional symptoms occur in 20-80% of cases
so can be missed by the patient and thus can not
be relied on for diagnosis.
 Fulminant myocarditis has abrupt onset, usually
within 2 weeks of a viral illness.Patients have
hemodynamic compromise requiring pressor or
mechanical support.
 Prognosis of fulminant myocarditis is good.

25.  A total of 147 patients (15 patients fulminant and
132 patients of acute myocarditis) were followed
for 5.6 years.
 Fulminant myocarditis was an independent
predictor of survival after adjusting for
age,histopathological findings and hemodynamic
variables.
N Engl J Med 2000;342:690-5

26. P<0.05
Long term transplant free survival did not differ significantly
according to the degree of inflammation on biopsy.
For fulminant myocarditis transplant-free survival of 93% in 11 years
N Engl J Med 2000;342:690-5

27.  Giant cell myocarditis have survival less than 6
months and is improved with the use of
immunosuppressive therapy.
 Giant cell myocarditis often have other
autoimmune disorders including thymoma and
Crohn disease.
 Chronic active myocarditis have insidious onset
and occurs in older adults.
 Eosinophilic myocarditis is a hypersensitivity to
drugs or occurs with systemic eosinophilic
disorders.

29. Suggestive of myocarditis 2 positive categories
Compatible with myocarditis 3 positive categories
High probability of myocarditis All 4 categories positive
Any matching feature in category =positive for category

30. Clinical symptoms-
 Clinical heart failure
 Fever
 Viral prodrome
 Fatigue
 Dyspnea on exertion
 Chest pain
 Palpitations
 Presyncope or syncope

31. Evidence of cardiac structural or functional defect in
the absence of regional coronary ischemia-
 Echocardiographic evidence of RWMA, cardiac dilation or
regional cardiac hypertrophy
 Troponin release: High sensitivity (> 0.1 ng/ml)
 Positive indium In 111 antimyosin scintigraphy
AND
 Normal coronary angiography OR,
 Absence of reversible ischemia by coronary distribution on
perfusion scan.

32. Cardiac magnetic resonance imaging-
 Increased myocardial T2 signal on inversion recovery
sequence
 Delayed contrast enhancement after gadolinium-DTPA
infusion

33. Myocardial biopsy-pathologic or molecular analysis –
 Pathologic findings compatible with Dallas criteria
 Presence of viral genome by PCR or in situ hybridization.

35.  Non-specific serum markers of inflammation
eg.ESR,CRP and leucocyte count are often
elevated in myocarditis but seldom used for
diagnosis.
 Increased serum concentration of cytokines
TNFα,IL1β and IL10 predict an increased risk of
death in myocarditis patients.
JACC 2004;44:1292-7
Heart 2004;90:464-70

36.  Anti-myosin antibodies are associated with LV
systolic dysfunction and diastolic stiffness in
patients with chronic myocarditis.
Lauer B et al,JACC 2000;35:11-18
 Anti-β1 receptor antibodies have been
associated with greater risk of death or heart
transplantation.
Stork S et al,Am Heart J 2006;152:697-704
 Approx. 59% patients of myocarditis in one study
were found to be positive for heart specific
antibodies by immunofluorescence.
Neumann DA et al,JACC 1990;16:839-46

37.  The diagnostic value of viral serology is limited
b/c most viral infections involved in the
pathogenesis of myocarditis are highly prevalent
in the general population.

38.  Troponins are more useful when high sensitivity
thresholds are used (> 0.1 ng/ml)
 A gradual rise of troponins over more than 24
hours,with a peak a day or more after the initial
rise,may help distinguish myocarditis from acute
ischemic injury.

39.  ECG may show sinus tachycardia,non-specific
ST-T abnormalities,ST elevation or pathologic Q
waves.
 Sensitivity of ECG for myocarditis is low (47%).
Am Heart J1992;124:455-67
 Widened QRS and presence of Q waves are
associated with higher rates of cardiac death or
heart transplantation.
Nakasima et al,Intern Med 1994;33:659-66
Nakasima et al,Jpn Heart J 1998;39:763-74

40.  There are no specific ECHO features of myocarditis
and it is used mainly to exclude other causes of
heart failure.
 Impaired right ventricular function is a strong
predictor of death or need for cardiac
transplantation in a series of 23 patients with
biopsy confirmed myocarditis.
Mendes LA et al, Am Heaert J 1994;128;301-7

41.  In the Myocarditis Treatment Trial,increased
sphericity and LV volume occurred in acute
active myocarditis.
 Fulminant myocarditis may be distinguished by a
smaller LV cavity size and increased wall
thickness.
Myocarditis Treatment Trial.Am Heart J1999;138:303-8
Felker et al, J Am Coll Cardiol 2000;36:227-32

42.  Cardiac MRI is being used with increasing
frequency for noninvasive assessment of patients
with suspected myocarditis.
 Cardiac MRI can evaluate 3 markers of tissue
injury –intracellular & interstitial edema (T2W)
hyperemia & capillary leakage (EGE) and
necrosis & fibrosis (LGE).
 A combination of T1-weighted and T2-weighted
images had the best combination of sensitivity
and specificity.

43.  A recent consensus report on CMRI in myocarditis
states that a cardiac MRI should be performed in
symptomatic patients with clinical suspicion of
myocarditis.
 Three imaging criteria for confirming the diagnosis
of myocarditis ( Lake Louise criteria) by cardiac
MRI have been proposed.
 At least two of the CMR criteria are required for
diagnosis of myocardial inflammation.

44. 1) Regional or global myocardial signaling intensity
increase in T2-weighted images.
2) Increased global myocardial early gadolinium
enhancement ratio b/w myocardium and skeletal
muscle in gadolinium enhancement T1W images.
3) At least one focal lesion with nonischemic regional
distribution in inversion recovery prepared
gadolinium enhanced T1W images (late gadolinium
enhancement).

45.  35 year male without any risk factors presented with 8 hrs
of chest pain,he was thrombolysed.Trop T was positive but
no RWMA on echocardiography.No culprit lesion on CAG.

46.  Delayed enhanced cardiac MRI showed extensive
hyper-enhancement sparing sub-endocardium
and not matching any coronary artery territory.

47.  Temporal evolution of
the distribution and
severity of LGE in
acute myocarditis.

50.  Contrast cardiac MRI may be used to direct
Endomyocardial biopsy.
 In this study by Mahrholdt et al,histopathological
evaluation of biopsy directed by contrast cardiac
MRI with LGE revealed active myocarditis in 19
of 21 patients.
 In contrast,when biopsy could not be obtained
from the region of contrast enhancement,active
myocarditis was found in only 1 of 11 patients.s
Mahrholdt H et al, Circulation 2004;109:1250-58

51.  Interestingly,CMR suggested that the lateral wall
may actually be the most common location for
lesion development,not the septum, from which
most of the biopsy samples have been taken
previously.

52.  Despite insensitivity for detection of myocarditis,
the Dallas criteria remain the gold standard for
unequivocal diagnosis.
 Chow and McManus demonstrated that with a
single EMB sample,histologic myocarditis could be
demonstrated in only 25% of cases.Even with 5
random samples,correct diagnosis by classic
Dallas criteria could be reached in only about
2/3rd of subjects.

53.  Recently ACC/ESC guidelines have described 2
clinical scenarios which has class I
recommendation for endomyocardial biopsy.
 First is the classic presentation of fulminant
myocarditis,ie. unexplained new-onset heart
failure symptoms < 2 weeks in duration associated
with normal or dilated LV and hemodynamic
compromise.
Circulation 2007;116:2216-2233

54.  Second scenario describes Giant cell myocarditis,
ie.unexplained new-onset heart failure symptoms
2 weeks to 3 months in duration associated with a
dilated LV and new ventricular arrhythmias,high
degree AV block or failure to respond to usual
care within 1 to 2 weeks.

55. DIAGNOSTIC MODALITY
SENSITIVITY
RANGE (%)
SPECIFICITY
RANGE (%)
Electrocardiographic changes (AV block; Q
wave, ST changes)
47 ?
Troponin (lower threshold of >0.1 ng/mL) 34-53 89-94
Creatine kinase MB isoform 6 ?
Antibodies to virus or myosin 25-32 40
Indium 111 antimyosin scintigraphy 85-91 34-53
Echocardiography (ventricular dysfunction) 69 ?
Cardiac magnetic resonance 86 95
Myocardial biopsy (Dallas criteria of
pathology)
35-50 78-89
Myocardial biopsy (viral genome by PCR) 38-65 80-100

57.  The first line of therapy for all patients with
myocarditis and heart failure is supportive care.

59.  111 patients of myocarditis and LVEF < 45% were
randomly assigned to conventional therapy alone
or combined with 24 weeks of immunosuppressive
therapy.

61. N Engl J Med 1997;336:1860-6

62. N Engl J Med 1997;336:1860-6

63.  These studies suggest that immunosuppression is
not beneficial in the routine treatment of acute
lymphocytic myocarditis.
 But,transplant-free survival in patients with
giant-cell myocarditis may be prolonged with a
combination of cyclosporine and corticosteroids.
Recommendation of HFSA 2010 guidelines-
Routine use of immunosuppressive therapies is not
recommended for patients with myocarditis. (Strength of
Evidence = A)

65. McNamara DM et al.Circulation 2001;103:2254-9 (IMAC II trial)

66.  Therefore,the routine use of IVIG for acute
myocarditis in adults is not recommended.
McNamara DM et al.Circulation 2001;103:2254-9 (IMAC II trial)

67. Drucker NA et al.Circulation 1994;89:252-7

68.  So, the IVIG may have a role in the treatment of
acute pediatric myocarditis.
Drucker NA et al.Circulation 1994;89:252-7

72.  Other approaches to modify immune
activation like immunoadsorption and
immunomodulation are under investigation.

74.  Acute myocarditis is an inflammatory disease of
the heart muscle that may progress to dilated
cardiomyopathy and chronic heart failure.
 The clinical presentation of acute myocarditis is
non-specific.
 Suspected myocarditis is currently confirmed
using advanced non-invasive imaging and
histopathologic examination.

75.  With the understanding of new pathophysiologic
mechanisms new therapies like interferon and
immune-modifying strategies are under
investigation.