SEMINAR 17/07/2013
DR PAWAN KUMAR OLA
 Acute myocarditis is an inflammatory disease of
the heart muscle that may progress to dilated
cardiomyopathy and chronic...
 According to WHO/ISFC myocarditis is an
inflammatory disease of the myocardium,diagnosed
by established histological,imm...
 Classic Dallas criteria for the pathologic diagnosis of
myocarditis require the presence of inflammatory
cells simultane...
H&E stain Acute myocarditis showing inflammatory cells
with myocyte damage
 Dallas criteria are limited by variability in
interpretation, lack of prognostic value and low
sensitivity.
 Alternativ...
CD3 immunostaining of T lymphocytes in acute
myocarditis
Herskowitz et al, JACC 1990;15:624-32
 The precise incidence of myocarditis is difficult
to ascertain.
 Recent pathologic series examining young adults
who ha...
 Viruses are the most common agents.
 The spectrum of viruses shifted from
coxsackievirus B to adenovirus in the late 19...
 Bowles & coworkers analyzed biopsy specimens from
624 patients with PCR and found overall viral
positivity was 38% (239/...
 Hepatitis C virus agent mainly seen in Asian countries
such as Japan (Hepatitis C infection is also overall
more prevale...
 Dobutamine may be associated with Eosinophilic myocarditis
as a hypersensitivity reaction.
Pathogenesis of myocarditis-
 Phase 1- cardiac injury and activation of the innate
immune response.
 Phase 2- acute myoc...
 Prog Cardiovasc Dis 2010;52:274-288
 Viruses enter cardiac myocytes or macrophages
through specific receptors and coreceptors.
 Receptor for coxsackievirus ...
Innate immune response
determines the acquired T
and B cell response.
CD4+T lymphocytes are
key mediators of cardiac
damag...
 Cardiac injury activates the innate
immune mechanisms like TLR2 &
TLR4.
 They induce proinflammatory
cytokines like TNF...
 Clinical presentation can range from asymptomatic
ECG or ECHO findings to cardiac dysfunction,
arrhythmias or heart fail...
 Acute myocarditis
 Fulminant myocarditis
 Giant cell myocarditis
 Chronic active myocarditis
 Eosinophilic myocardit...
 The viral prodrome of fever, chills, myalgia and
constitutional symptoms occur in 20-80% of cases
so can be missed by th...
 A total of 147 patients (15 patients fulminant and
132 patients of acute myocarditis) were followed
for 5.6 years.
 Ful...
P<0.05
Long term transplant free survival did not differ significantly
according to the degree of inflammation on biopsy.
...
 Giant cell myocarditis have survival less than 6
months and is improved with the use of
immunosuppressive therapy.
 Gia...
Suggestive of myocarditis 2 positive categories
Compatible with myocarditis 3 positive categories
High probability of myoc...
Clinical symptoms-
 Clinical heart failure
 Fever
 Viral prodrome
 Fatigue
 Dyspnea on exertion
 Chest pain
 Palpit...
Evidence of cardiac structural or functional defect in
the absence of regional coronary ischemia-
 Echocardiographic evid...
Cardiac magnetic resonance imaging-
 Increased myocardial T2 signal on inversion recovery
sequence
 Delayed contrast enh...
Myocardial biopsy-pathologic or molecular analysis –
 Pathologic findings compatible with Dallas criteria
 Presence of v...
 Non-specific serum markers of inflammation
eg.ESR,CRP and leucocyte count are often
elevated in myocarditis but seldom u...
 Anti-myosin antibodies are associated with LV
systolic dysfunction and diastolic stiffness in
patients with chronic myoc...
 The diagnostic value of viral serology is limited
b/c most viral infections involved in the
pathogenesis of myocarditis ...
 Troponins are more useful when high sensitivity
thresholds are used (> 0.1 ng/ml)
 A gradual rise of troponins over mor...
 ECG may show sinus tachycardia,non-specific
ST-T abnormalities,ST elevation or pathologic Q
waves.
 Sensitivity of ECG ...
 There are no specific ECHO features of myocarditis
and it is used mainly to exclude other causes of
heart failure.
 Imp...
 In the Myocarditis Treatment Trial,increased
sphericity and LV volume occurred in acute
active myocarditis.
 Fulminant ...
 Cardiac MRI is being used with increasing
frequency for noninvasive assessment of patients
with suspected myocarditis.
...
 A recent consensus report on CMRI in myocarditis
states that a cardiac MRI should be performed in
symptomatic patients w...
1) Regional or global myocardial signaling intensity
increase in T2-weighted images.
2) Increased global myocardial early ...
 35 year male without any risk factors presented with 8 hrs
of chest pain,he was thrombolysed.Trop T was positive but
no ...
 Delayed enhanced cardiac MRI showed extensive
hyper-enhancement sparing sub-endocardium
and not matching any coronary ar...
 Temporal evolution of
the distribution and
severity of LGE in
acute myocarditis.
 Contrast cardiac MRI may be used to direct
Endomyocardial biopsy.
 In this study by Mahrholdt et al,histopathological
e...
 Interestingly,CMR suggested that the lateral wall
may actually be the most common location for
lesion development,not th...
 Despite insensitivity for detection of myocarditis,
the Dallas criteria remain the gold standard for
unequivocal diagnos...
 Recently ACC/ESC guidelines have described 2
clinical scenarios which has class I
recommendation for endomyocardial biop...
 Second scenario describes Giant cell myocarditis,
ie.unexplained new-onset heart failure symptoms
2 weeks to 3 months in...
DIAGNOSTIC MODALITY
SENSITIVITY
RANGE (%)
SPECIFICITY
RANGE (%)
Electrocardiographic changes (AV block; Q
wave, ST changes...
 The first line of therapy for all patients with
myocarditis and heart failure is supportive care.
 111 patients of myocarditis and LVEF < 45% were
randomly assigned to conventional therapy alone
or combined with 24 week...
N Engl J Med 1997;336:1860-6
N Engl J Med 1997;336:1860-6
 These studies suggest that immunosuppression is
not beneficial in the routine treatment of acute
lymphocytic myocarditis...
McNamara DM et al.Circulation 2001;103:2254-9 (IMAC II trial)
 Therefore,the routine use of IVIG for acute
myocarditis in adults is not recommended.
McNamara DM et al.Circulation 2001...
Drucker NA et al.Circulation 1994;89:252-7
 So, the IVIG may have a role in the treatment of
acute pediatric myocarditis.
Drucker NA et al.Circulation 1994;89:252-7
 Other approaches to modify immune
activation like immunoadsorption and
immunomodulation are under investigation.
 Acute myocarditis is an inflammatory disease of
the heart muscle that may progress to dilated
cardiomyopathy and chronic...
 With the understanding of new pathophysiologic
mechanisms new therapies like interferon and
immune-modifying strategies ...
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
Acute Myocarditis:Diagnosis and Management
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Acute Myocarditis:Diagnosis and Management

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Seminar on Acute myocarditis for Medical professionals and students

Published in: Science, Health & Medicine

Acute Myocarditis:Diagnosis and Management

  1. 1. SEMINAR 17/07/2013 DR PAWAN KUMAR OLA
  2. 2.  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.
  3. 3.  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
  4. 4.  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
  5. 5. H&E stain Acute myocarditis showing inflammatory cells with myocyte damage
  6. 6.  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
  7. 7. CD3 immunostaining of T lymphocytes in acute myocarditis Herskowitz et al, JACC 1990;15:624-32
  8. 8.  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
  9. 9.  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
  10. 10.  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
  11. 11.  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.
  12. 12.  Dobutamine may be associated with Eosinophilic myocarditis as a hypersensitivity reaction.
  13. 13. 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
  14. 14.  Prog Cardiovasc Dis 2010;52:274-288
  15. 15.  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.
  16. 16. 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
  17. 17.  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
  18. 18.  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.
  19. 19.  Acute myocarditis  Fulminant myocarditis  Giant cell myocarditis  Chronic active myocarditis  Eosinophilic myocarditis  Peripartum cardiomyopathy
  20. 20.  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.
  21. 21.  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
  22. 22. 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
  23. 23.  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.
  24. 24. 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
  25. 25. Clinical symptoms-  Clinical heart failure  Fever  Viral prodrome  Fatigue  Dyspnea on exertion  Chest pain  Palpitations  Presyncope or syncope
  26. 26. 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.
  27. 27. Cardiac magnetic resonance imaging-  Increased myocardial T2 signal on inversion recovery sequence  Delayed contrast enhancement after gadolinium-DTPA infusion
  28. 28. Myocardial biopsy-pathologic or molecular analysis –  Pathologic findings compatible with Dallas criteria  Presence of viral genome by PCR or in situ hybridization.
  29. 29.  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
  30. 30.  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
  31. 31.  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.
  32. 32.  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.
  33. 33.  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
  34. 34.  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
  35. 35.  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
  36. 36.  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.
  37. 37.  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.
  38. 38. 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).
  39. 39.  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.
  40. 40.  Delayed enhanced cardiac MRI showed extensive hyper-enhancement sparing sub-endocardium and not matching any coronary artery territory.
  41. 41.  Temporal evolution of the distribution and severity of LGE in acute myocarditis.
  42. 42.  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
  43. 43.  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.
  44. 44.  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.
  45. 45.  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
  46. 46.  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.
  47. 47. 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
  48. 48.  The first line of therapy for all patients with myocarditis and heart failure is supportive care.
  49. 49.  111 patients of myocarditis and LVEF < 45% were randomly assigned to conventional therapy alone or combined with 24 weeks of immunosuppressive therapy.
  50. 50. N Engl J Med 1997;336:1860-6
  51. 51. N Engl J Med 1997;336:1860-6
  52. 52.  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)
  53. 53. McNamara DM et al.Circulation 2001;103:2254-9 (IMAC II trial)
  54. 54.  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)
  55. 55. Drucker NA et al.Circulation 1994;89:252-7
  56. 56.  So, the IVIG may have a role in the treatment of acute pediatric myocarditis. Drucker NA et al.Circulation 1994;89:252-7
  57. 57.  Other approaches to modify immune activation like immunoadsorption and immunomodulation are under investigation.
  58. 58.  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.
  59. 59.  With the understanding of new pathophysiologic mechanisms new therapies like interferon and immune-modifying strategies are under investigation.

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