Sandro Sponga, MD, PhD

CardioThoracic Dept.

Udine University Hospital

Italy

ACQ Congress

Florence 02 May 2017

Ex-vivo Cardiac Preservation

December 3, 1967

Louis Washkansky

1° allogenic man-to-man

transplant

Jean-Francois Borel

Cyclosporine

Machine Perfusion

Cardiac Preservation

LifeCradle®

(Organ Transport Systems, Houston, Texas)

Heart Transporter™ (Organ Recovery Systems, Des Plains, Illinois)

OCS

Organ Care System™ (Transmedics, Andover, Massachusetts)

Cardiac Reconditioning

Graft Evaluation Graft Manipulation

Cold Warm

• No contemporary evidence of any successful

clinical heart transplant with this strategy

• There is historical evidence for ex-situ

transportable hypothermic perfusion with 4

successful transplants from standard criteria

DBD donors (Cape Town, SA)

Hypothermic Blood Perfusion

Historical Hypothermic Blood Perfusion

Annals of Surgery 1973 178:687

Non-pulsatile, low pressure, asanguinous cold perfusion (3 ºC)

No intracellular oedema

Interstitial oedema did not correlate with graft survival

Historical Hypothermic Blood Perfusion

Historical Hypothermic Blood Perfusion

Hypothermic Blood Perfusion: devices

Hardesty, Griffith, et. al

Univ. of Pittsburgh Medical Center

Robicsek, et. al

Charlotte Memorial Hospital

Historical Warm Blood Perfusion

Historical Warm Blood Perfusion

Organ Care System console • Easy to use

• Function > 20 hr with 6 batteries

• Robust & Lightweight

• Portable

Heart Solution Set Infused into blood circulation in order to optimize heart perfusion

Heart Perfusion Module •Advanced sterile circuit designed for biocompatibility

•Integrated components enable single motion installation

•Contains reliable pre-calibrated sensors

•Seamlessly integrates between 2 operating modes

•Enables sterile Arterial / Venous blood sampling

Wireless Monitor Controls and Displays all aspects of heart perfusion

Transmedics Organ Care System™

Remote area organs recruitment

Transmedics Organ Care System™

OCS – How it works?

• Haemodynamic ECG, Heart Rate (HR)

Aortic Pressure (AOP)

Coronary Blood Flow (CF)

Aortic Blood Flow (AOF)

Coronary Sinus Saturation

PA Pressure (PAP)

• Metabolic Serial lactate levels

Arterial and venous differential

Pulsatile

Pump

ORGAN CHAMBER

Blood

Warmer

RV Oxygenator

Exit via PA

RA

Blood

Reservoir

AORTA

Good case Recipient Donor

• 38 yrs, Female, Caucasian

• 170 cm, 70 kg, B Rh +

• HELLP syndrome, Eclampsia, DIC

• CoD: Cerebral Hemorrhage

• Hospital: Lecco

• Hemodynamics:

– SR 95 bpm

– ABP 110/80 mmHg

– Hct 38% (16 PRC, 3000 ml FFP)

• Dopamine 7-8 /kg/min

• Echo

– Normal wall motion/function

– Normal dimension/septum thickness

– Minimal pericardial effusion

• No cath

• Ventilatory support

• 59 yrs, Male, Caucasian

• 170 cm, 67 kg, B Rh +

• Former smoker

• DCM, NYHA Class III

• Medical history:

– Total heart block (PM/ICD, 2004)

– Post-traumatic epilepsy (1993)

– Struma, normal thyroid function (2008)

• Hemodynamics:

– 60 bpm

– ABP 120/70 mmHg

• No ventilatory support, no VAD

• No urgency status

• On WL since 3½ mos

Hemolysis, Elevated Liver enzyme levels and a Low Platelet count

OCS™ Perfusion Parameters

0

10

20

30

40

50

60

70

80

90

100

0 20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 320

Time (mins)

0

200

400

600

800

1000

AOP (mmHg) HR (BPM) CF (ml/min)

Lactate (mmol/L) A V

1,3

3

1,2

1

1,4

4

1,4

5

1,2

2

1,1

7

1,3

9

1,4

6

1,93

2,08

1,84

2,07

Intra-operative Course Cardioplegia St Thomas II, 500 cc

CPB time 137 min (54 min assistance)

Off pump first attempt

Hemodynamics ABP 110/60 mmHg, CVP 6 mmHg

No pacing/defibrillation

Intra-op echo normal wall motion/function EDD 45 mm PWD 8 mm

ESD 25 mm IVSD 10 mm

EDV 81 ml EF 74%

ESV 21 ml SF 44%

Inotropes dobutamine 2.4 /kg/min

isoprenaline 0.01 /kg/min

Overall ischemic time

Without OCS™ 443 min

With OCS™ 106 min

Recipient Donor

• 18 yrs, Female, Caucasian

• 160 cm, 60 kg, 0 Rh +

• CoD: Head trauma (heavy road accident)

• Hospital: Taranto

• Hemodynamics:

– SR 100 bpm

– ABP 125/70 mmHg

– Hct 32%

• Dopamine 5 /kg/min

• Echo

– Normal wall motion/function

EDD 44 mm PWD 11 mm

EF 76% IVSD 11 mm

– No valve pathologies

• No cath

• Ventilatory support

• 59 yrs, Male, Caucasian

• 170 cm, 67 kg, B Rh +

• Former smoker

• DCM, NYHA Class III

• Medical history:

– Total heart block (PM/ICD, 2004)

– Post-traumatic epilepsy (1993)

– Struma, normal thyroid function (2008)

• Hemodynamics:

– 60 bpm

– ABP 120/70 mmHg

• No ventilatory support, no VAD

• No urgency status

• On WL since 3½ mos

Bad case

OCS™ Perfusion Parameters

0

20

40

60

80

100

120

140

160

180

200

0 30 60 90 120 150 180 210 240 270 300 330 360 390 420 450

Time (mins)

AO

P / H

R

0

100

200

300

400

500

600

700

800

900

CF

AOP (mmHg) HR (BPM) CF (ml/min)

2,5

2,8

1

3,7

9

6,3

1 6,6

7,8

1

5,4

6,4

5,0

7 5,7

6,5

1,7

9

2,4

52

,35

2,6

4

3,8

5

4,9

7

6,5

1 6,8

7,8

8

1,9

8

Lactate (mmol/L) A V

Ann Thorac Surg, 2014

Indication to OCS

OCS: Udine experience

Donor Recipient

OCS time Cold

Isch.time Tot

Isch time Age Risk Factors Age Risk factors

1 34 58 150 103 253

2 38 HELLP sdr 59 330 105 435

3 46 CAD 43 Redo 88 194 282

4 52 59 174 134 308

5 54 54 ECMO 306 110 416

6 57 CAD, age 62 209 126 335

7 38 Cardiac arrest Expected IT > 5h

51 306 116 422

8 57 Age 58 148 131 379

9 33 Prolonged cardiac arrest 60 355 158 513

10 45 Expected IT > 5h 57 ECMO 388 130 518

11 50 Expected IT > 5h 57 ECMO 350 134 484

12 43 Expected IT > 5h + cardiac arrest 59 Infected LVAD+

Emergency 305 120 425

13 44 Espected IT >5 h 58 Infected LVAD

Emergency 287 138 425

14 39 Cardiac arrest, Troponine, DIC, liver failure 66 ECMO, Redo Emergency

115 80 195

15 45 Expected IT > 5 h 58 ECMO

Mean time 261,23 130,69 399,62

HELLP: Hemolysis, Elevated Liver enzymes, Low Platelet count

Non utilised graft

RCA traumatic dissection 2007

Ephinephrine bolus 2008

Disconnection OCS-Aorta

2011

9 hours out of body time 2012

- PROCEED II trial: non inferiority study

- Better myocardial preservation has never been demonstrated in humans

with OCS

AIM of the Study Evaluate better myocardial protection with OCS

Propose OCS as gold standard in heart transplantation to prevent

primary graft failure, early mortality, and possibly expand the donor pool

Italian Health Ministry Grant

Past

Hypothermic anaerobic organ storage organ time up to 4-6 hours

reducing myocardial energy consumption

slowing loss of high-energy substrates.

Current

Few advancements over the past 25 years. Current preservation solutions:

still lead to time dependent ischemia- reperfusion injury

underutilization of the current consented donor pool

unpredictable outcomes

Ischemia Time: the largest modifiable risk factor for Heart

Transplant outcome

0

0,5

1

1,5

2

30 60 90 120 150 180 210 240 270 300 330 360

Ischemia time (minutes)

p < 0.0001

Re

lati

ve

Ris

k 5

-yr

mo

rta

lity

ULT HEART TRANSPLANTS (1/2002-6/2008)

Risk Factors for 1-yr and 5-yr mortality

J Heart Lung Transplant

2008; 27: 937-83

30 heart donors randomized 1:1

15

Cold storage

15

OCS

Exclusion criteria: borderline donors, controindication to OCS, donors from

Udine

Minimal sample size: 3-5 patients in each group for biologial data

12-20 patients in each group for clinical data

Study design

Myocardium will be sampled

at time of

organ harvesting,

before implantation

after reperfusion

Blood samples, at declamping time from

CVC, coronary sinus and OCS

Additional procedures

Clinical data

AIM 1: Clinical outcomes:

-Survival, EGF, ECMO/IABP, PM, ICU stay, Inotropic score -

Haemodynamic data (CI, SAP, PAP, CVP, WP)

-Echocardiographic data (LVEF, RV function, TAPSE)

-Laboratory data (lactate, troponin, CK-MB, BNP)

9 8 7 6 5 4 3 2 1 0Chemical Shift (ppm)

0

0.05

0.10

0.15

No

rma

lize

d In

ten

sity

Residual

H2O

Referencestandard

1H NMR spectrum of a human bio-fluid

Metabolic data

AIM 2: metabolic outcomes with (1H NMR) spectroscopy :

-metabolic processes (glycolysis, gluconeogenesis, lipid metabolism).

-impaired myocardial energetics (phosphocreatine/ATP ratio and

ATP/inorganic phosphate ratio).

-new perfusion protocols for OCS

Biological data

AIM 3: Histological outcomes (histology immunofluorescence, cellular,

molecular and electron microscopy (EM):

-ischemia-reperfusion injury

inflammation

autophagy

DNA or cytoplasm damage

rejection

-Sarcomeres, mitochondria and sarcolemma (EM)

-Micro RNA markers of myocardial damage (ST2, miR1, miR133a,

miR133b, miR499-5p, miR122 and miR375)

p16INK4A

DAPI

𝛼SA

gH2A.X

Ki67

DAPI

𝛼SA

gH2A.X

Ki67

DAPI

A living organ outside the body:

a new unique model

No systemic

adverse effects

High concentration

Long time infusion

Effect limited to the graft

Virus transfection and

immunotherapy Employing immunotherapy developed for tumor,

antigens exposed by the donor heart can be

modified to reduce rejection

Bodreau et al Molecular Therapy (2011)

Reduction of

Rejection

Infection

Tumor

CAV

• Gene editing

• Immunogenic modulation

• ↓ acute and chronic rejection

• ↓ Immunosuppression and side effects

• Xenotransplantation

The old dream ……

xenotransplantation

The organ factory The organ factory

Circulatory death:

Italy 20 minutes

Australia 10 min

Canada 5 minutes

USA 5 minutes (Pittsburg

Protocol)

Boucek 75 sec

Experience with DCD hearts

• Resuscitated human cadaver heart and transplanted it into a baboon

• First heart Tx was technically a DCD donor heart

• 3 DCD hearts used in paediatric heart transplants with good outcomes, all alive at 6 months; Denver, USA

• Human DCD heart successfully resuscitated using extracorporeal perfusion

2008

2009

1966

1967

DCD inclusion criteria

44

•Maastricht Category III donors

•< Age 40

•No history of cardiac disease, prior cardiac surgery or significant

cardiac trauma

•Low dose inotrope/vasopressor – NA < 0.2 mcg/kg/min

•Stable haemodynamics MAP > 60 and CVP < 10 mmHg

•Maximum warm ischemic time of 30 min

DCD Protocol

45

• Ischemic time < 30 min

• Transfer to OR

• Very rapid blood retrieval from RAA with dual-stage cannula (better

and rapid drainage and decompression of abdominal organs

• During blood collection aortic cross clamp

• Anterograde perfusion: 1l of ST Thomas cardioplegia

• OCS instrumentation

47

DCD Retrievals

N=24

Did Not Progress

N = 8

Asystole within

30min

N=16

Not Transplanted

N=5

Poor Lactate

N=3

OCS Failure

N=2

Transplanted

N=11

DCD Clinical update

•DCD HTx series from St vincents Hospital, Sydney 11 patients

remain well at home with normal biventricular function

•DCD HTx series from Papworth Hospital , Cambridge and

Harefield Hospital, London, UK make a combined DCD

HTx recipient cohort of 37 at end of 2016

Metabolic

Resuscitation

OCS Optimizes:

Perfusion

Substrate & Hormones

Assessment

OCS Enables:

Metabolic/Perfusion

Functional

Echo coronary Coronary

Coronary angiography

Reduction in

Ischemia

OCS Maintains Hearts in:

Oxygenated perfusion state

Donors

Results

Transmedics Organ Care System

Thank you

A good head and a good heart are always a formidable combination.

N. Mandela