Miocardite a cellule

giganti prima del

trapianto di cuore:

possibili opzioni

terapeutiche

L'esperienza di Niguarda

Enrico Ammirati

Cardiologia 2

ASST Grande Ospedale

Metropolitano Niguarda

Enrico Ammirati, MD, PhD

GIANT CELL MYOCARDITIS BEFORE TRANSPLANTATION

- POSSIBLE THERAPEUTIC OPTIONS

Enrico Ammirati, MD, PhD

‘De Gasperis’ Cardio Center

Transplant Center

ASST Grande Ospedale

Metropolitano Niguarda

Milan, Italy

NO POTENTIAL CONFLICTS

of INTEREST for this lecture

INTRODUCTIONINTRODUCTION

• Giant cell myocarditis (GCM) is a rare disorder in which

survival beyond 1 year without Heart transplantation

(HTx) is uncommon.1

• GCM is attributed to a T-cell mediated inflammation of the

myocardium.2myocardium.

• The most common early manifestation is acute heart

failure (HF )(range from 31 to 64%).3,4

1. Maleszewski/Cooper LT, AJC 2015

2. Cooper LT, NEJM 1997

3. Kandolin R, CIRC HF, 2013

4. GCM Study Group, JACC 2003

INTRODUCTIONINTRODUCTION

• GCM is associated with autoimmune disorders (20%):

celiac disease, inflammatory bowel disease (IBD), lupus,

thyroiditis,….1,2

• GCM is a disease of relatively young (mean age 43 ±13

years).1years).

• Similar incidence in female and male.1

1. Cooper, LT NEJM 1997

2. Kandolin R, CIRC HF, 2013

INTRODUCTIONINTRODUCTION

• Endomyocardial biopsy (EMB) is needed for final diagnosis

of GCM.1

• EMB is underutilized in the setting of fulminant

myocarditis (FM):2 only in 26% of patients with FM on

vaECMO in an Italian registry (N=57). Steroids were usedvaECMO in an Italian registry (N=57). Steroids were used

only in 18%.2

• 0 EMB in a single center experience of 22 cases of FM on

vaECMO in Japan.3

1. Caforio AL., ESC 2013

2. Lorusso, R, Ann Thorac Surg 2016

3. Nakamura, J Intens Care 2015

USEFULNESS of USEFULNESS of

IMMUNOSUPPRESSIONIMMUNOSUPPRESSION

Multicenter US

Am J Cardiol 2008

• Only 5 patients with LVEF<25%:

• In pts with LVEF<25% Transplantation free survival: 20%

Am J Cardiol 2008

USEFULNESS of USEFULNESS of

IMMUNOSUPPRESSIONIMMUNOSUPPRESSION

NIGUARDA EXPERIENCENIGUARDA EXPERIENCE

20022002--20162016

129 of Myocarditis

40 cases of FM

FM: transplantation

Non fulminant myocarditis 100%

Fulminant myocarditis 72.5%

FM: transplantation

free survival 72.5%

1015

2140

FulminantMyocarditis

305880

89NF Myocarditis

No. at risk

6

4

15

7

YEARS 1 3 5 7 9

Log Rank (Mantel-Cox) p<0.0001

Ammirati E, Submitted

NIGUARDA EXPERIENCENIGUARDA EXPERIENCE

20022002--20162016

40 cases of FM: 5 (12%) cases were GCM.

– 3 HTx during hospitalization

– 1 death during hospitalization

– 1 full recovery after 21 days on vaECMO. (Need for ICD due to – 1 full recovery after 21 days on vaECMO. (Need for ICD due to

VT after discharge despite LVEF 60%)

• Overall survival: 80%

• Transplantation-free survival: 20%

NIGUARDA EXPERIENCENIGUARDA EXPERIENCE

20022002--20162016

USEFULNESS of USEFULNESS of

ANTIANTI--THYMOCYTE GLOBULINTHYMOCYTE GLOBULIN

Harefield, UK

Am J Cardiol 2015

• Transplantation free survival: 50%

THERAPY USED IN GCM IN PATIENTS ON vaECMO

Author and year ECMO duration Final outcome Immunosuppresive

treatment regimen

Journal

Hazebroek, MR -2013

11 days Biventricular assist device and subsequent heart transplantation (HTx)

methylprednisolone + cyclophosphamide

International journal of cardiology

Yeen, WC - 2011 8 days Recovery anti-thymocyteglobulin + cyclosporin+ methylprednisolone

Interactive cardiovascular and thoracic surgery

Le Guyader, A -2006 4 days HTx No Interactive

12

Le Guyader, A -2006 4 days HTx No immunosuppressivetreatment

Interactive cardiovascular and thoracic surgery

Ankersmit, HJ - 2006 7 days Recovery anti-thymocyteglobulin + cyclosporin+ prednisolone

The Thoracic and cardiovascular surgeon

Toscano, G - 2014 15 days HTx cyclosporin + methylprednisolone + azathioprine

Transplant International

Ammirati, E - 2015 21 days Recovery anti-thymocyteglobulin + cyclosporin+ methylprednisolone

Journal of Cardiovascular Medicine

A CLINICAL CASE:

Mr A.D.• A 31-year-old man with a history of multiple autoimmune

disorders (thyroiditis, ulcerative colitis, autoimmune

hepatitis)

– Influenza-like illness 1 week before onset of cardiac symptoms

– progressive dyspnoea and severe biventricular dysfunction (left

Day 1

– progressive dyspnoea and severe biventricular dysfunction (left

ventricular ejection fraction –LVEF- of 30%)

– Coronary angiogram was normal (SUSPECTED MYOCARDITIS)

– VT treated with electrical cardioversion

– After 24 hrs TRANSFERRED TO OUR CENTRE (HTx/MCS

REFERRAL CENTRE in Milan)

CLINICAL AND ECHO DATA

BP: 85/40 mmHg with Dopamine

HR 122 bpm � + Epinephrine

SatO2 90% � NIMV

ECHO: LVEF 20%,EDD 53 mm MR ++

IVS 12 PW 12 mm, RV: TAPSE 16 mm

No pericardial effusion

Day 2

No pericardial effusion

No aortic regurgitation

SU

ND

AY

NIG

HT

ABG analysis pH 7.4 Lactate 7

BP 80/40 HR 135 bpm

OLIGURIA 70 ml/2hrs (<0.5 ml/kg/hr)

UNRESPONSIVE cardiogenic shock

after 48hrs since the onset

1:1 IABP +A 0.12+D in CCU

THE DAY AFTER

Morning, 19th November 2012:BP 105/50 mmHg HR 105 bpm on IABP + Adrenaline + Dopamine

CVP 8 mmHg T 37.2°C

Urinary output >100 ml/h ABG: lactate 1.5

Day 3

NT-proBNP 32,126 ng/L (n.v. 0-121)

Troponin T hs 2,065 ng/L (n.v. 0-14)

C-reactive protein 24.6 (n.v. 0-0.5 mg/dL)

WHITE BLOOD COUNT 15.5*109/L

Creatinin 1.26 mg/dL (n.v. 0.7-1.2)

ALT 127 U/L (n.v. 3-45)

SEVERE MYOCARDIAL INJURY

SYSTEMIC INFLAMMATORY

RESPONSE

RENAL and HEPATIC

INJURY

ENDOMYOCARDIAL BIOPSY

multinucleated giant cells widespread inflammatory infiltrate

20th November: Tuesday morning (72hrs after the first hospital admission): RV biopsy

Tuesday 4 p.m. histological diagnosis: Giant-cell Myocarditis

Day 4

HEMODYNAMIC PROFILE:

UNSTABLE

HEMODYNAMIC PROFILE:

UNSTABLE

VENTRICULAR ARRHYTHMIASVENTRICULAR ARRHYTHMIAS

EMB: GIANT-CELL MYOCARDITIS +

EMB: GIANT-CELL MYOCARDITIS +

HIGH RISK

Day 4

IABP +

Inotropic agents

SEVERE LV±RV DYSFUNCTION

+ MARKERS OF NECROSIS

SEVERE LV±RV DYSFUNCTION

+ MARKERS OF NECROSIS

SYSTEMIC ORGAN DAMAGE

SYSTEMIC ORGAN DAMAGE

HIGH RISK

MYOCARDITISElectrical

cardioversion +

i.v. amiodarone

Need for NIMV

Renal and

hepatic damage

LVEF 10%

Severe RV

dysfunction

+ Troponin T

2,065 ng/L

INTENSIVE SUPPORTDay 4

Repeated Sustained VT �TRANSFERRED

to CARDIAC INTENSIVE UNIT

Hemodynamically unstable on IABP �

HD A + Noradrenaline + Intubation +

Mechanically assisted ventilation

20thNovember 4p.m.

Report of the EMB:

GIANT-CELL MYOCARDITISGIANT-CELL MYOCARDITIS

5:15 p.m. OPERATING THEATER

Femoral Veno-arterial

Extracorporeal membrane

oxygenation (va-ECMO)

IABP+inotropic agents

Va ECMO (CO: >4 L/min) positioned 20/Nov Extubated 1 day after surgery

Combined Immunosuppression:1gx3days methylprednisoloneRATG 2.5mg/kg in 1 weekCyclosporine 200 mg/d (basal level 200)

EMB:GCM

Blood group BHTx Listing

8/Dec.:LVEF 50%

ECMO removal11/Dec: 21 days

CR

P (

mg

/d

l)

10

15

20

25

LVEF 10%

HTx screening

HTx ListingNATIONAL URGENCY5�8/Dec

12/DecIABPremoval

CR

P (

mg

/d

l)

19/11/12-15:00

20/11/12-07:00

22/11/12-07:00

24/11/12-07:00

27/11/12-07:00

30/11/12-07:00

03/12/12-07:00

09/12/12-07:00

14/12/12-07:00

0

5

10

19

/N

ov

/2

01

2

20

/N

ov

/2

01

2

24

/N

ov

/2

01

2

22

/N

ov

/2

01

2

27

/N

ov

/2

01

2

30

/N

ov

/2

01

2

3/

De

c/

20

12

14

/D

ec

/2

01

2

9/

De

c/

20

12

WEANING AND FURTHER

INVESTIGATIONS

ECMO and IABP were removed after day 21

After additional 11 days the patient was

discharged

(Hospital stay 34 days)

Viral Abs: All NEGATIVE

� HHV6, CMV, EBV, HSV 1/2, VZV,

� Adenovirus, Coxsackie A9, A24, B 1-6,

� Parvovirus B19, echovirus

Bacterial: Chlamydia pneumoniae, Borrelia

Burgdorferi, Mycoplasma pneumoniae

Antibody serum testing: POSITIVE: anti-nDNA (1:160), anti-dsDNA,

ANA (1:320 homogeneous pattern) � Suspected LUPUS

IMMUNOSUPPRESSIVE REGIMEN

Induction

Methylprednisolone (Solumedrol) i.v. 1 g qd x 3 days

Thymoglobuline i.v. 70 mg (1 mg/kg, day 1) + 56 mg

(0.8 mg/kg day 4) + 45 mg (0.6 mg/kg, day 7) [with CD (0.8 mg/kg day 4) + 45 mg (0.6 mg/kg, day 7) [with CD

3+ T cell count monitoring]

Cyclosporine 35 mg bd (day 2), 50+75 mg (day 3)+ 75

mg bd (day 4), 75+100 mg (day 5)

IMMUNOSUPPRESSIVE REGIMEN

Maintenance

Methylprednisolone i.v. 60 mg qd � 35 mg � oral

prednisone 35 mg

Cyclosporine (S. Neoral) Dosage 3-5 mg/kg/dieCyclosporine (S. Neoral) Dosage 3-5 mg/kg/die

CARDIOVASCULAR MR

One week after discharge (4 January 2013)

LVEF 60%

NTproBNP 1.591 ng/L

CARDIOVASCULAR MR

LGE in the

subepicardium

Diffuse myocardial oedema in the mid-

sub-epicardium in T2-weithed STIR

sequences

Diffuse areas of late gadolinium

enhancement (LGE)

• Cardiac function may recover completely in GCM

� but circulatory support (IABP+ECMO) to maintain

hemodynamics and oxygenation

• Immunosuppression may require days or weeks to

CAVEATs

• Immunosuppression may require days or weeks to

allow resolution of myocardial damage and

transplant-free survival

�but no specific raccomandation regarding drug

combination/dosage/duration

�Some studies suggest efficacy of combined

immunosuppresive regimen including

thymoglobulines

Increased risk of ventricular arrhythmias after GCM (consider ICD if ventricular arrhythmias are documented – 59% of GCM

transplant-free survivors experienced a sustained VT).1

Risk of recurrence of GCM when immunosuppressive

agents are weaned off (documented recurrence of GCM in native

CAVEATs

heart3 and also documented in Htx).1

Risk of subsequent dilated cardiomyopathy (DCM)(Transplant free survival: 69% at 1 year, 52% at 5 years ,1 in the GMC

Study Group: 22% at 5 years)2

2. Kandolin R, CIRC HF, 2013

4. Cooper, AJC 2008

3. GMC Study Group, JACC 2003

• Suspect the diagnosis of fulminant myocarditis due to GCM

(AHF+VT+ high levels of troponin)

• Transfer patients with unstable hemodynamics to

HTx/MCS centres

• Institute rapidly IABP and vaECMO if needed

CONCLUSIONS

• Confirm diagnosis of GCM by EMB

• Treat GCM with combined immunosuppression including

thymoglobines

• Enlist the patient if no recovery after 2 weeks or

complications due to vaECMO

Team:

M. Frigerio

M. Cipriani/

A. Garascia/

F. Oliva

HF Specialists

““DE GASPERISDE GASPERIS”” CARDIO CENTERCARDIO CENTERNIGUARDA CANIGUARDA CA’’ GRANDA HOSPITALGRANDA HOSPITAL

P. Gagliardone

Anesthetist

E. Bonacina

Pathologist

P. Pedrotti

CMR specialist

C.F.Russo

Cardiac Surgeon