Hội Tim mạch học Việt Nam

Some points updated on
myocarditis
Nguyen Ngoc Quang, MD, FASCC
Dept. of Cardiology, Hanoi Medical University
Vietnam National Heart Institute


1. Epidemiology
✓ True incidence of myocarditis in community is unknown
✓ Greatest burden of myocarditis (chronic DCM, then die
or require orthotopic heart transplantation) may not be
apparent for 6-12 years after diagnosis
50

Underlying Causes and Long-Term Survival in Patients with Initially
Unexplained Cardiomyopathy.
Felker GM, et al. N Engl J Med 2000; 342:1077-1084

9
IDCM

Myocarditis

7
Ischemic

5

4

4

4

3

3

Infiltrative

Peripartum

HTN

HIV

CTD

Abuse


A

B

C

Symptom threshold

Active
myocarditis

Left ventricular
function

Normal

Poor

Clinical
syndrome of
heart failure

Severe

Normal

Time

Years

In Review, Lancet, 2009


2. Etiology
✓ Viral & postviral myocarditis: major causes of acute and chronic
dilated cardiomyopathy

✓ Spectrum of viruses (EMB samples) shifted from coxsackievirus B to adenovirus to parvovirus B19 and other viruses.

✓ Less frequent viruses: hepatitis C, EBV, CMV and HIV.

Coxsackie B
Coxsackie A

1948

Other
Many
Adenovirus
Enterovirus Uncommon
HCV
Viruses

Enteroviruses

HHV6
EBV

PVB19

2010
Non-Enteroviruses


Many injuries can cause
myocarditis
•
•
•
•
•

•
•

Viruses- changing spectrum
Toxins- Doxorubicin
Radiation
Hypersensitivity Reactions
Drugs, Vaccines
Bacterial, fungal, protozoal Infections
Genetic predisposition in 20% or more


Some special etiology
✓ Hypersensitivity myocarditis: anticonvulsants,
antibiotics, and antipsychotics.

✓Eosinophilic myocarditis: Churg–Strauss syndrome,
Loffler’sendomyocardial fibrosis, cancer, and parasitic,
helminthic, or protozoal infections and with vaccination
for several diseases, including smallpox.

✓ Giant-cell myocarditis (acute dilated
cardiomyopathy): thymoma, autoimmune disorders,
ventricular tachycardia, or high-grade heart block.


Major causes of myocarditis
✓ Infectious causes ✓ Noninfectious causes
✓ Viral
✓ Cardiotoxins:

✓ Bacterial
✓Catecholamines, Anthracyclines, Cyclophosphamide,
✓ Spirochetal
Heavy metals (copper, lead, iron), Arsenic,
✓
✓ Mycotic
✓ Alcohol, Cocaine, Carbon monoxide,Methysergide
✓ Rickettsial
✓ Hypersensitivity reactions:
✓ Protozoal
✓ Helminthic
✓ Antibiotics, Diuretics, Dobutamine; Lithium; Tetanus toxoid;

Clozapine; Methyldopa
✓ Insect bites (bee, wasp, spider, scorpion, Snake)
✓ Systemic disorders
✓ Collagen-vascular diseases, Sarcoidosis, Celiac disease,
Kawasaki disease, Hypereosinophilia, Wegener's granulomatosis,
Thyrotoxicosis
✓ Inflammatory bowel disease (Crohn's disease, ulcerative colitis)
✓ Radiation


3. Pathophysiology
Progression from acute injury to chronic DCM: 3-stage process:
✓ Acute injury leads to cardiac damage (myocyte death)
within hours of viral cell entry, results from direct viral damage
tomyocytes

✓

Exposure of intracellular antigens (cardiac myosin) and an
innate immune response comprised of altered regulatory T cell
function, NK cells, interferon gamma, nitric oxide…

✓ Heart specific immune response characterized by antibodies
to pathogen, host cardiac proteins and autoreactive T cells.

Most recover with few consequences, a minority die from
arrhythmias or progress onto chronic HF


Immune Pathogenesis
of Chronic DCM
Acute Myocarditis
Innate Immunity/TLRs
Anti-viral response
Cytokines (TH1/TH2/TH17)

Autoimmunity
T and B cell Mimicry
Recognition of Myosin
by Immune System

Chronic Myocarditis
Autoreactive
T cells and Autoantibodies
Antibody Mediated
Cell Signaling in the Heart

Relapsing and Remitting
Autoimmunity
Epitope Spreading

Dilated Cardiomyopathy


Pathogenesis of DCM After Enteroviral Infection
Coxsackie B virus

Myocyte infection
Days

“Normal heart”

Necrosis
Apoptosis
Innate immunity

Myocyte cytoskeletal damage
Direct cytopathic effect

Myocyte cell death

Weeks

• Autoantibodies
• Autoreactive
• T lymphocytes

?

Acute dilated
cardiomyopathy

Months
to years

Sequestered
viral genome

Hemodynamic
remodeling
Neurohumoral
activation

Cooper LT, Gersh BJ. Am J Card, 2002

Apoptosis
Chronic dilated cardiomyopathy

CP1184045-6


4. Clinical Presentations
✓ Viral prodrome and highly variable symptoms
✓ Children often have fulminant presentation.
✓ Common clinical presentation
✓ Acute Heart Failure with Dilated Cardiomyopathy
✓ Syncope: poor prognosis if related with VT or AVB

✓ Fulminant heart failure after viral syndrome:
better prognosis but require hemodynamic support

✓ Chest pain: good prognosis


5. Diagnostic procedures
✓ Troponin I: specificity 89%, sensitivity 34%
✓ ECG: sensitivity: 47%
✓ Endomyocardial biopsy
✓ Echocardiography: to distinguished fulminant myocarditis
✓ Cardiovascular magnetic resonance
✓ Analysis of messenger RNA and protein markers
✓...


US Centers for Disease Control
Case Definitions for Myocarditis
• Possible- Clinical syndrome with typical EKG
changes, and troponin rise or abnormalities on
echocardiogram

• Probable- Criteria for possinle myocarditis and
NEW changes on echocardiogram

• Confirmed- Positive histology
MMWR 2003


Typical Electrocardiogram

Acute Myocarditis

I

aVR

V1

V4

II

aVL

V2

V5

III

aVF

V3

V6

Sensitivity ~42%

Morgera 1992

2:1 Second degree HB and Q waves
In Acute Myocarditis

Nakashima 1998


Comparison of the Sensitivity and Specificity of
Troponin and Heart Biopsy for Myocarditis

Specificity
(%)

Positive
predictive
value

Negative
predictive
value

Technique

No.

Sensitivity
(%)

Troponin T

80

53

96

93

56

Troponin I

88

34

89

–

–

EMB-H and E

71

10-36

98

–

–

EMB-Immunoperoxidase

20

80

85

–

–

Skouri et al: JACC 48(10):2085, 2006
CP1256539-1


Endomyocardial Biopsy
EMB Indication (Class I, LOE B)

• New onset heart failure
• of 2 weeks to 3 months duration
• assoct. w a dilated left ventricle,
• new ventricular arrhythmias,
• 2nd or 3rd degree heart block
• failure respond to usual care
within 1 to 2 weeks

Cooper, LT, et al Circulation 2007


Histologic “Dallas” Criteria

Sampling error, Variation in interpretation, Low
sensitivity, Lack of correlation with outcome
Aertz, et al Am J Pathol 1986
Baughman, K, Circulation 2006


Endomyocardial Biopsy
Giant Cell Myocarditis

When to Suspect Giant Cell
Myocarditis
• Failure to Respond to Usual
Care
• Ventricular Tachycardia
• High-grade Heart Block

Cooper, LT, et al AHJ Dec 2008


Giant Cell versus Lymphocytic Myocarditis
Transplant-Free Survival
Proportion surviving

1.0

LM group
GCM group

0.8
0.6
0.4
0.2
0
0

1

2

3

Survival (yr)

4

5

Cooper, LT, NEJM 1997


Death or Transplant
P=0.0005

Event free of death
or transplant

1.0

Trial

0.8
0.6
0.4
0.2

Control

0
0

100

200

300

400

Days
Cooper, LT, et al Am Heart Journal 2008


Consensus Criteria on the CMR
Diagnosis of Myocarditis
Endorsed by SCMR

Myocardial Inflammation Requires 2 of 3
1. IR prepared T2 weighted images (body coil),
the regional or global intensity ratio of myocardium
to skeletal muscle exceeds 2SD (1.9)
2. T1 global enhancement ratio is greater than 2SD (4.5)
3. T1 “Late enhancement” post-contrast has
at least one focal lesion with
non-ischemic distribution
Friedrich, M., Presented ESC September 2008, JACC 2009


CMR in Acute Myocarditis
Triple-inversion-recovery
T2 weighted Spin echo CMR

T1 weighted fast spin echo

T1 inversion recovery
Skouri et al: JACC 48(10):2085, 2006


Antimyosin and Gallium Imaging in
Rheumatic Carditis

Indium-111
Antimyosin

Aschoff Nodule, 10x, 40x
Gallium-67

Enteroviral Infection & Clinical Outcome
Mortality in Myocarditis/
DCM Patients (%)

Proportion Surviving
Enterovirus
negative

1.0
1.0
0.9
0.9
0.8
0.8
0.7
0.7
0.6
0.6
0.5

25

25

20

P=0.02

P=0.02

15
10

Enterovirus
positive

5

4

0
0

4

8

12

16

20

24

28

Enteroviral RNA+

Enteroviral RNA-

Months

Detection of enteroviral RNA in pt with myocardial
disease is associated with an adverse prognosis and
is an independent predictor of outcome
Why HJ: Circ, 1994
Terasaki F: J Card Surg, 1999