any inflammation of the myocardium -myocarditis

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1. Myocarditis
Definition: any inflammation of the
myocardium

2. INTRODUCTION
Major cause of SCD < 40 yrs ( 20 %)
Myocardial inflammation in 1 to 9 percent of
routine postmortem examinations.
Cause of Dilated cardiomyopathy in 9% cases

4. Important Causes of Myocarditis
Infection
Viral
Bacterial, rickettsial, spirochetal
Protozoal, Metazoal
Fungal
Toxic
anthracyclines, catecholamines, Interleukin-2, alpha
interferon
Hypersensitivity

5. Viral Infection
Coxsackie (A, B)
Echo
Influenza (A, B)
Polio
Herpes simplex
Varicella-zoster
Epstein-Barr
Cytomegalovirus
Mumps
Rubella
Rubeola
Vaccinia
Coronavirus
Rabis
HBV, HCV
Arbovirus
Junin virus
Human
immunodeficiency

6. Bacterial, rickettsial, spirochetal
Corynebacterium
diphtheriae
salmonella typhi
Beta-hemolytic
streptococci
Neisseria meningitidis
Legionella pneumophila
Listeria monocytogenes
Camphylobacter jejuni
Coxiella burnetii (Q
fever)
Chlamydia trachomatis
Mycoplasma
pneumoniae
Chlamydia psittaci
(psittacosis)
Rickettsia rickettsii
(Rocky Mountain spotted
fever)
Borrelia burgdorferi
(Lyme disease)
Mycobacterium
tuberculosis

7. Protozoal, Metazoal, Fungal
Protozoal
Trypnosoma cruzi
(Chagas’ disease)
Toxoplasma gondi
Metazoal
Trichinosis
Ehinococcosis
Fungal
Aspergillosis
Blastomycosis
Candidiasis
Coccidioidomycosis
Cryptococcosis
Histoplasmosis
Mucormycosis

8. Drugs Causing
Hypersensitivity Myocarditis
Antibiotics
amphoericin
B
ampicillin
chlorampheni
col
penicillin
tetracycline
streptomycin
Sulfonamides
sufadiazine
sufisoxazole
Anticonvulsants
phenindione
phenytoin
carbamazepine
Antitubercuous
isoniazid
paraaminosalicylate
Anti-inflammatory
indomethacin
oxyphenbutazone
phenylbutazone
Diuretics
acetazolamide
chlorthalidone
hydrochlorothiaz
ide
spironolactone
Other
amitriptyline
methyldopa
sulfonylureas
tetanus toxoid

9. Pathological distribution -112 consecutive biopsy-
confirmed myocarditis at the Massachusetts
General Hospital :
lymphocytic 55%
Borderline 22%
granulomatous 10%
giant cell 6%
Eosinophilic 6%

10. Etiological agents
Previously enteroviruses, mainly
Coxsackie
Recently adenoviruses, parvoviruses, and
cytomegaloviruses more common.
In Japan, HCV infection more common,
associated with HCM

11. Pathophysiology
Several mechanisms of myocardial
damage
(1) Direct injury by infectious agent
(2) Injury by toxins like Corynebacterium
diphtheriae
(3) Infection induced immune reaction or
autoimmunity.

12. Pathophysiology
Triphasic disease process
Phase I: Viral Infection and Replication
Phase 2: Autoimmunity and injury
Phase 3: Dilated Cardiomyopathy

13. Phase I: Viral Infection and
Replication
Coxsackievirus B3 (prototype) causes
infectious phase
Lasts 7-10 days
Characterized by active viral replication
Initial myocyte injury, release of antigenic
intracellular components i.e myosin into
bloodstream

14. Phase 2: Autoimmunity and
injury
Local release of cytokines (interleukin-
1, 2, 6, TNF, and NO stimulating T-cell
reaction
Cause reversible myocardial
depression

15. Phase 2: Autoimmunity and
injury
Cell mediated injury & autoantibodies
against myocyte components
Antigenic mimicry
Apoptosis

16. Phase 3: Dilated
Cardiomyopathy
Persistent viruse growth cause myocyte
apoptosis.
Cytokine activate matrix
metalloproteinases (gelatinase,
collagenases, and elastases)
Adverse remodeling and progressive heart
failure

19. Morphology (Gross)
Cardiac dilation
Myocardium flabby, pale,
with focal hemorrhages

20. Normal Myocardium

21. Borderline Myocarditis

22. Active Myocarditis

23. Toxoplasma.

24. True Bacteria
myocarditis.

25. Giant cell myocarditis
“Fiedler’s” myocarditis
MN giant cells
Lymphocytes, eosinophils, necrosis
Differential: Sarcoid, hypersensitivity, TB
Aggressive clinical course with poor
prognosis: indication for transplant
Median survival 6 months after diagnosis

26. Giant cell.

27. Hypersensitivity myocarditis
Interstitial infiltrate of macrophages,
eosinophils
No or little necrosis
No granulomas, but multinucleated cells may
be present
Fewer clinical manifestations than other
forms of myocarditis
Associated with long list of drugs (classically,
methyldopa)

28. Eosinophils.

29. Clinical Manifestations
Most cases of acute myocarditis are clinically
silent
60% of pts have antecedent flulike symptoms
Large number identified by heart failure
symptoms
35% of pts with myocarditis and HF have chest
pain
May mimic an acute MI with ventricular
dysfunction, ischemic chest pain, ECG
evidence of injury or Q waves

30. Clinical Manifestations
May present with syncope, palpitation with AV
block or ventricular arrhythmia
May cause sudden death
May present with systemic or pulmonary
thromboembolic disease

31. Clinical Findings
Physical Examination
-Tachycardia, hypotension, fever and tachycardia
disproportionate to the degree of fever
-Bradycardia rarely, and a narrow pulse pressure
-Murmurs of mitral or tricuspid regurgitation
-S3 and S4 gallops
-Distended neck veins, pulmonary rales, wheezes,
gallops, and peripheral edema may be detected

32. Lieberman’s clinicopathological
classification
Fulminant
Subacute
Chronic active
Chronic persistent

33. Fulminant Acute Chronic
active
Chronic
persistent
Symptom
onset
Distinct Indistinct CHF,
LV dysfunction
Indistinct
CHF, LV
dysfunction
Indistinct
Clinical
presentation
Cardiogenic
shock, severe LV
dysfunction
Non-CHF
symptoms,
normal LV
function
Initial biopsyMultifoci of active
myocarditis
Active or
borderline
myocarditis
Active or
borderline
myocarditis
Active or
borderline
myocarditis
Clinical natural
history
Complete
recovery or death
Incomplete
recovery or
dilated CM
Dilated CM Non-CHF
symptoms,
normal LV
function
Histologic
natural history
Complete
resolution of
myocarditis
Complete
resolution of
myocarditis
Ongoing or
resolving
myocarditis,
fibrosis
Ongoing or
resolving
myocarditis
Immunosuppr
essive therapy
No benefit Sometimes
beneficial
No benefit No benefit

34. Fulminant myocarditis
The patient usually toxic in appearance, often requires high-dose
vasopressor support or even a ventricular assist device (VAD).
Triad of hemodynamic compromise, rapid onset of symptoms
(usually within 2 weeks), and fever.
Echo-severe global ventricular dysfunction but minimally dilated left
ventricles.
Endomyocardial biopsy-multiple foci of inflammation and necrosis
but does not match the clinical phenotypic severity.
Significant reversible cardiac depression.
Long term prognosis good

35. Expanded Criteria for Diagnosis
of Myocarditis
Suspiciousfor myocarditis = 2 positive
categories
Compatiblewith myocarditis = 3 positive
categories
High probabilityof being myocarditis = all
4 categories positive

36. Category I: Clinical Symptoms
Clinical heart failure
Fever
Viral prodrome
Fatigue
Dyspnea on exertion
Chest pain
Palpitations
Presyncope or syncope

37. Category II: Evidence of Cardiac
Structural/Functional Perturbation in the
Absenceof Regional Coronary Ischemia
Echocardiography evidence –RWMA, Cardiac
dilation, Regional cardiac hypertrophy
Troponin release -High sensitivity (>0.1 ng/ml)
Positive indium-111 antimyosin scintigraphy
Normal coronary angiography orAbsence of
reversible ischemia by coronary distribution on
perfusion scan

38. Category III: Cardiac Magnetic
Resonance Imaging
Increased myocardial T2 signal on
inversion recovery sequence
Delayed contrast enhancement following
gadolinium-DTPA infusion

39. Category IV: Myocardial
Biopsy—Pathological or
Molecular Analysis
Pathology findings compatible with Dallas
criteria
Presence of viral genome by polymerase
chain reaction or in situ hybridization

40. Diagnostic Modality Sensitivity Range Specificity Range
ECG changes (e.g., AV
block, Q, ST changes)
47% ?
Troponin (lower threshold of
>0.1 mg/ml)
34%-53% 89%-94%
CK-MB 6% ?
Antibodies to virus or
myosin
25%-32% 40%
Indium-111 antimyosin
scintigraphy
85%-91% 34%-53%
Echocardiography
(ventricular dysfunction)
69% ?
Cardiac magnetic
resonance imaging
86% 95%
Myocardial biopsy (Dallas
criteria of pathology)
35%-50% 78%-89%
Myocardial biopsy (viral
genome by PCR)
38%-65% 80%-100%

41. Blood studies
> 4 fold rise in IgG titer (4-6 wk) to document
an acute viral infection
Heart specific antibodies nonspecific

42. Electrocadiogram
sinus tachycardia is most common
diffuse ST-T wave changes
myocardial infarction pattern
conduction delay and LBBB in 20%
complete heart block causing Stokes-Adams
attacks (particularly in Japan), but rarely
require a permanent pacer
supraventricular and ventricular arrhythmias

43. Myocarditis
H9925 9-8-98

44. H9925 8-30-98

45. Echocardiography
Useful tool in managing patients with
acute myocarditis
LV systolic dysfuntion, segmental WMA
LV size typically normal or mildly dilated
wall thickness increased
ventricular thrombi( 15%)
Mitral or tricuspid regurgitation

46. Tissue characterisation and tissue doppler
Monitor course of the illness and response
to therapy

47. Diagnostic Studies
Chest radiograph
-Mild to moderate cardiomegaly
-Pericardial effusion
-Venous congestion and pulmonary
edema in severe cases

48. Diagnostic Studies
Radionuclide ventriculography
-accurate estimate of chamber volumes, left and right
ventricular ejection fractions
Myocardial imaging
-Gallium-67 imaging -> active inflammation of the
myocardium and pericardium
-Indium-111 monoclonal antimyosin antibody imaging
-> detecting myocyte injury in patients
Positive antimyosin scan and nondilated left ventricular
cavity (LVEDD 62 mm) highly predictive for detecting
myocarditis on biopsy.

49. Diagnostic Studies
Contrast media-enhanced MRI
Accurate tissue characterization by measuring T1 and T2 relaxation
times and spin densities.
Early myocardial enhancement focal. Later global enhancement,
baseline within 90 days.
Focal myocardial enhancement + RWMA –myocarditis
New contrast MR techniques (segmented inversion recovery
gradient-echo pulse sequences, early and late gadolinium
enhancement) differentiates between diseased and normal
myocardium
Identifies patients who should undergo biopsy
Facilitates guided approach to the abnormal region of myocardium
for biopsy.

50. Diagnostic Studies
Cardiac catheterization
-Elevated LVEDP & volumes
-CAG-normal coronary arteries.

51. Diagnostic Studies
Endomyocardial biopsy
-gold standard for the diagnosis of
myocarditis
ACC/AHA guidelines for the treatment of heart failure -
class IIb
Dallascriteria
-Active myocarditis (an inflammatory infiltrate + injury to
the adjacent myocytes)
-Borderline myocarditis (infiltrate not accompanied by
myocyte injury)

52. Indications for Endomyocardial
Biopsy
Exclusion of potential common etiologies of dilated cardiomyopathy
(familial;ischemic; alcohol; postpartum; cardiotoxic exposures) and
the following:
Subacute/ acute symptoms of heart failure refractory to standard
management
Worsening EF despite optimal therapy
Hemodynamically significant arrhythmias ( progressive heart block
and ventricular tachycardia)
Heart failure with concurrent rash, fever, or peripheral eosinophilia
History of collagen vascular disease
New-onset cardiomyopathy in presence of known amyloidosis,
sarcoidosis, or hemachromatosis
Suspicion for giant cell myocarditis (young age, new subacute heart
failure, or progressive arrhythmia without apparent etiology)

53. Limitations of endomyocardial
biopsy (EMB).
Sampling error.
4 to 6 biopsy samples routinely performed
Careful postmortem analysis of proven myocarditis
cases demonstrated 17 samples necessary to correctly
diagnose myocarditis in 80% cases.
This number of biopsies not feasible in clinical practice,
so the lack of sensitivity of EMBs is apparent.
Intraobserver variability another significant limitation in
histopathological diagnosis

54. Molecular detection techniques for viral genome
(in situ hybridization for viral genetic signatures
or multiplexed PCR amplification of the RNA
increases sensitivity.
Analysis of immunological activation on the
biopsy tissues (inflammatory cell infiltration
subtypes, signal activation, cytokine and
complement signals, upregulation of MHC
antigens

55. Natural history
50% chronic ventricular dysfunction
25% progress to transplantation or death
25% spontaneous recovery
Fulminant myocarditis 90% event-free survival
rate
Giant cell myocarditis 20% survival at 5 years
HIV associated myocarditis worst prognosis.

56. Predictors of poor prognosis
Presentation with syncope, bundle branch block,
or an EF 40%
Advanced heart failure symptoms (NYHA
classes III or IV)
Elevated left ventricular filling pressures
Pulmonary hypertension
Enteroviral RNA presence on EMB
Giant cell myocarditis

57. Triphasic disease process.

58. Treatment
First-line therapy -supportive care
Hemodynamic support (vasopressors to
intraaortic balloon pump to VADs)
Heart failure treatment-(diuretics, i/v
vasodilators in acute stage, ACE inhibitors or
ARB’s and beta blockers, as soon as they are
clinically stable)
Immunosuppressive regimens doubtful efficacy

59. Immunosuppressive trials
limitations
(1) High degree of spontaneous improvement in
the control and treatment arms
(2) Small sample size with a heterogeneous
collection of recruited patients
(3) Patchy nature of myocardial biopsy detection of
myocarditis
(4) Lack of relationship between pathological
abnormalities and clinical prognosis

60. Immunosuppressive therapy
Not routinely considered
Indications
1.Giant cell myocarditis
2.Autoimmune or hypersensitivity reactions
3.Patients with severe hemodynamic compromise
and deteriorating conditions
4.Best responders -active autoimmune response
without persisting viral genome

61. phase III trial of interferone therapy suggest
significant improvement in both symptoms and
ventricular function
no indication for immunoglobulins, except
pediatric population and those refractory to
immunosuppressive therapy
Immune Adsorption Therapy –no definite role
Immune modulation-Autologous blood irradiated
with ultraviolet radiation, reinjected back into the
patient, decrease markers of inflammation.