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Severe Myocarditis: A 2012 update… Alain Combes Service de Réanimation iCAN, Institute of Cardiometabolism and Nutrition Hôpital Pitié-Salpêtrière, AP-HP, Paris Université Pierre et Marie Curie, Paris 6 www.reamedpitie.com

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Page 1: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Severe Myocarditis:

A 2012 update…

Alain Combes

Service de Réanimation

iCAN, Institute of Cardiometabolism and Nutrition

Hôpital Pitié-Salpêtrière, AP-HP, Paris

Université Pierre et Marie Curie, Paris 6www.reamedpitie.com

Page 2: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Conflict of interest

Principal Investigator: HEROICS trial HVHF after complicated heart surgery NCT01077349 Sponsored by GAMBRO

Principal Investigator: EOLIA trial VV ECMO in ARDS NCT01470703 Sponsored by MAQUET, Getinge Group

Received honoraria from MAQUET, Getinge Group

Page 3: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Definition - Etiologies

«Myocarditis» is defined as inflammation of the heart muscle

Histology: cellular infiltrate and myocyte necrosis

Etiologies:

Infectious diseases• Viruses: Coxsackie, Adenovirus, HIV, CMV, Hep B

Parvovirus B19, HHV6, (H1N1)

• Bacteria

• Parasites (Toxoplasma, Chagas)

• Fungi

Hypersensitivity (Drugs)

Autoimmune and systemic diseases • Lupus, Wegener, Eosinophilic, Sarcoidosis, Giant cell

Myocardial toxins (Cocaine, chemotherapy)

Peripartum

Page 4: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

6.3 millions military recruits over 25 yrs 126 non-traumatic sudden deaths, autopsy performed 10% of myocarditis-related deaths

Page 5: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Clinical manifestations

From asymptomatic EKG abnormalities to overt cardiac failure…

Clinical features: Preceding viral illness, flu-like syndrome Fever Chest pain, mimicking acute coronary syndromes Tachycardia Arrhythmia Sudden death:

• 10% of cases (Eckart, AnnIntMed, O4)

Clinical signs of heart failure• Minimal, slow evolution • Fulminant, leading to refractory cardiogenic shock in a

few days

Page 6: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

EKG

EKG findings

Sinus tachycardia

Diffuse ST-T wave abnormalities

Prolonged QT interval

Bundle branch block (LBBB++)

Myocardial infarction pattern

Complete heart block

Supraventricular tachyarrhythmias

Ventricular tachyarrhythmias

May be normal…

Page 7: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

EKG mimicking AMI

Page 8: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

EKG: LBBB

Page 9: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Laboratory Findings

Page 10: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Biology: Troponin (Smith, Circ, 97)

Page 11: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Many patients with acute/fulminant myocarditiswill undergo coronary artery angiography…

Page 12: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Other laboratory findings

Non specific tests Leucocytosis/leucopenia, Eosinophilia+++ Mononucleosic syndrome Sedimentation rate, CRP, PCT…

Specialized tests Virological diagnosis

• Serology (limited value)• Cultures: throat and stools• PCR (blood, CSF, tissues)

Inflammation:• Antinuclear Ab, ANCA, Angiotensin Conversion Enzyme

Research tests Autoantibodies (mitochondria, myosin, b-receptor) Immunohistochemical myocardial studies (research)

Page 13: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Doppler

Echocardiography

Page 14: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Fulminant myocarditis

Markedly decreased LV EF

Near normal LV dimension

Increased septal thickness

Acute myocarditis

Markedly decreased LV EF

Dilated LV

Normal septal thickness

Page 15: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Doppler Echocardiography

Other findings Regional wall motion abnormalities

Diastolic dysfunction

Change in echocardiographic image texture:• Increased brightness

• Heterogeneity

Thrombi

Pericardial effusion

Page 16: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Cardiac MRI…

The new diagnostic gold standard?

Page 17: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Cardiac MRI

Combination of

T1-weighted and T2-weighted

Gadolinium contrast-enhanced MRI +++

Visualize localization, activity and extent of inflammation

One or several foci in the myocardium

Foci most frequently located in lateral free wall

Frequent subepicardial lesions

Can guide myocardial biopsies+++

Page 18: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 19: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Still indication for

myocardial biopsies?

Page 20: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Histology: Dallas Criteria

3 histological grades (Aretz, Hum Pathol, 87)

Active Myocarditis :

• Cellular infiltrate +, myocyte necrosis +

Borderline Myocarditis :

• Cellular infiltrate +, myocyte necrosis -

Negative Biopsy :

• Cellular infiltrate -, myocyte necrosis -

Distribution and diffusion of the cellular infiltrate Focal, confluent or diffuse

Mild, moderate, severe

However, low to moderate sensitivity/specificity

Page 21: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Histology: Dallas Criteria

Borderline Active

Page 22: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 23: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 24: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Grade 1, Level B:

.

Page 25: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Prognosis

Page 26: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

PrognosisMcCarthy, NEJM, 2000

Survival without transplantation

P=0.05

(15 patients)

(132 patients)

Page 27: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 28: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

2003 - 2009

41 patients refractory cardiogenic shock due to fulminant myocarditis

Mean age 38±12 years

66%, women

Mechanical assistance

Thoratec BiVAD (n=6) or

ECMO (n=35)

Page 29: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 30: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Long term survival: 68%

4 (10%) patients had heart transplantation

Independent predictors of ICU death determined at admission:

SAPS II >56 (OR, 10.23) and troponin Ic >12 microg/L (OR, 7.49)

Page 31: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Complete follow-up for 26 survivors

Median follow-up was 525 [92–2400] days

Mean LVEF was 57±9%

≥60% for 12 non-transplant and all 4 transplanted

40–60% for 10 nontransplanted survivors

21 patients had percutaneous femoral ECMO

10 still complained of paresthesia/peripheral

neurological defect

2 had persistent leg ischemia requiring surgical repair

for 1 and amputation for the other

Page 32: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

0

10

20

30

40

50

60

70

80

90

100

PhysicalFunctioning

Role-physical

BodilyPain

General Health

Vitality Social Functioning

Role-Emotional

Mental Health

* * * *

Page 33: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Relatives of dying ICU patients

ICU patients

Myocarditis

Type II diabetics

10

20

30

40

50

60

HAD-A HAD-D

70

Score

≥8,

(%)

Page 34: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 35: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 36: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Treatment

Page 37: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Treatment

Supportive care always indicated Bed rest, Diuretics, vasodilators ACE inhibitors, angiotensin-receptor blockers Aldosterone antagonists b-blockers, (with caution in the acute phase) Immunosuppressors if specific disease Vasopressors/inotropic agents in case of shock

Mechanical assistance +++ May be urgently needed if fulminant form or rapid

deterioration of hemodynamic status Patients should rapidly be transferred to experienced

centers Bridge to recovery:

• ECMO+++, First line assistance (Heart transplantation)

Page 38: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Long term survival: 68%, 4 (10%) patients had heart transplantation

Independent predictors of ICU death determined at admission:

SAPS II >56 (OR, 10.23) and troponin Ic >12 g/L (OR, 7.49)

Page 39: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Myocarditis Treatment Trial

111 randomized patients, LVEF<45% Histologically proven myocarditis Immunosuppression protocol Placebo vs prednisone + Cyclosporine or

azathioprine

Mason, NEJM, 1995

Page 40: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

IV immune globulinMcNamara, Circ, 2001

62 patients with DCM, randomized, LVEF<40%

Placebo vs IVIg

P = NS

Page 41: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Specific/Novel treatments

Immunosuppression

First line therapy if• Giant cell

• Systemic autoimmune diseases

Corticosteroids

Cyclosporine, Tacrolimus

Azathioprine

Immunomodulation/Stimulation

IV Immune globulins

Interferon

Antiviral agents, vaccination

Page 42: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Tailored immune-modulating strategiesLiu, Circ, 2001

Phase I Phase II Phase III

Page 43: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Immunomodulation vs

Immunosuppression

b-Interferon for patients with entero-adenovirus myocardial persistance Kuhl, Circ, 2003 22 patients, LV Dysfunction, viral genome + Interferon: virus clearance, improved LVEF

Immunosuppressants: prednisone+imurel Frustaci, Circ, 03

• 41 patients, active myocarditis, LV Dysfunction• 21 responders, 20 non responders• Responders: AutoAb +, viral genome -

Wojnicz, Circ 01• 84 patients DCM, HLA overexpressed on myocytes• Treatment 3 months• EF improvement in treated patients: 71% vs 31%

Page 44: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 45: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 46: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 47: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 48: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 49: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 50: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,
Page 51: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

Conclusion

Myocarditis is a rare and severe condition

Especially the fulminant form

Diagnosis based on clinical features, EKG, Echo, Troponin, MRI

Myocarditis can mimic acute coronary syndromes

Mechanical circulatory assistance may be urgently needed if rapid hemodynamic deterioration

Immunosuppression during the acute phase

Giant cell

Systemic autoimmune diseases

Significant progresses in the understanding of the pathophysiology of the disease in recent years

Help design tailored immune-modulating strategies

Page 52: A 2012 update… - Critical Care Canada · Conclusion Myocarditis is a rare and severe condition Especially the fulminant form Diagnosis based on clinical features, EKG, Echo, Troponin,

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