Transplantation A Half Century of Progress

April 6, 2019

David D’Alessandro, M.D. Surgical Director, Cardiac Transplantation and Mechanical Circulatory Support Disclosures

• None

2

Heart Transplantation

• How did we get there? • How far have we come? • Where are we going? The danger of touching the heart

"Surgery of the heart has probably reached the limits set by Nature to all surgery. No method, no new discovery, can overcome the natural difficulties that attend a wound of the heart."

Stephen Paget, 1896

• published his technique for the vascular anastomosis in 1902 • 1905 reported heterotopic kidney and in dogs • Nobel Prize in Physiology 1912 History of Cardiac History Evolution of CPB Early Challenges in 1920s - 1950s

• Multiple failed attempts at operative treatment of rheumatic mitral stenosis • Poor visualization during ASD repairs

Tubbs dilator Heart Lung Machine John Gibbon

1953 Cecilia Brevolek: May 6th as the first successful truly open-heart operation performed with the use of a heart-lung machine. Surg Forum 1960;11:18.

• First human cardiac transplant was a chimpanzee xenograft performed at the University of in 1964. Operative Permit

Public ridicule

“…not only immoral, but amoral”.

• 1966 Lower performed “a reverse Hardy” • Passed up an opportunity to perform a human to human transplant in 1966 due to over cautious concern about secondary incompatibility

Louis Washkansky (December 3, 1967) “My moment of truth – the moment when the enormity of it all really hit me – was just after I had taken out Washkansky’s heart. I looked down and saw this empty space… the realization that there was a man lying in front of me without a heart but still alive was, I think, the most awe-inspiring moment of all.” Christiaan Barnard

History of Heart Transplantation US Experience

• Adrian Kantrowitz performed the first pediatric heart transplant (19 day old) on December 6, 1967. – Recipient lived for about 6 hours. • Shumway performed the first adult human-to-human heart transplant in the US at Stanford on January 6, 1968. – Recipient lives 15 days. • Denton Cooley succeeds in Houston on June 1968. 5 more the same month and several more the same year. History of Heart Transplantation US Experience

• 100 transplants performed in 1968. • 18 transplants performed in 1970. • By 1971, 146 of the first 170 heart transplant recipients were dead.

History of Heart Transplantation

• Establishment of brain death (Tucker v. Lower) • Introduction of transvenous endomyocardial biopsy by Philip Caves in 1973 provided a reliable means for monitoring allograft rejection • Introduction of Cyclosporine History of Heart Transplantation

• Cyclopsorine A • First preclinical study on porcine model published in the Lancet in 1978 • Introduction of cyclosporine dramatically increased patient survival and marked the beginning of the modern era of successful cardiac transplantation in 1981 – By 1985 1, 3 and 5 year survival had reached 83%, 75% and 70%.

UNOS Policy

• United Network for Organ Sharing established in 1977, divided into 11 regions • Organizations (OPO) • Status 1A – mechanical circulatory support 30 days, device failure, intubation, high-dose single inotrope or multiple inotropes with PA catheter • Status 1B – VAD, single inotrope, can be at home • Status 2 – stable outpatients • Status 7 – inactive • Only 25% transplants performed since 1998 have been in Status 2 candidates New Transplant listing

32 Regions Toyoda et al. Circ J 2013; 77: 1097 – 1110.

Heart Transplantation

Bi-atrial Bi-caval Adult and Pediatric Heart Transplants Kaplan-Meier Survival (Transplants: January 1982 – June 2016)

Median survival = 11.1 years; Median survival conditional on surviving to 1 year = 13.7 years 100

75

50 N = 132,494 Survival (%) 25

0 0 1 2 3 4 5 6 7 8 9 101112131415161718192021222324252627282930313233 Years 2018

JHLT. 2018 Oct; 37(10): 1155-1206 Adult Heart Transplants Kaplan-Meier Survival by Era (Transplants: January 1982 – June 2016) 100 1982-1991 (N=21,482) 1992-2001 (N=40,097) 75 2002-2008 (N=26,046) 2009-6/2016 (N=30,824)

50

Survival (%) All pair-wise comparisons were significant at p < 0.0001. 25

Median survival (years): 1982-1991=8.6; 1992-2001=10.5; 2002-2008=12.4; 2009-6/2016=NA 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Years 2018

JHLT. 2018 Oct; 37(10): 1155-1206 Indications for Transplant

• AHA/ACC Stage D CHF with no cardiac improvement with surgical or medical therapy • Reduced left ventricular ejection fraction and a reduced functional exercise capacity (V02) with results <10 mL/kg/min or < 11-15 mL/kg/min (or 55% predicted) and major limitation of the patient’s daily activities with achievement of anaerobic metabolism • Refractory angina and inoperable CAD • Refractory malignant arrhythmias • Benign inoperable primary cardiac tumor Adult Heart Transplants Diagnosis

2% 3% 46% 3% CHD 3% 50% 4% HCM 3% 1% 1% 2% ICM 3% 2% NICM RCM 3% Retransplant VCM Other 41% 33%

1/1982 – 6/2017 1/2009 – 6/2017

2018

JHLT. 2018 Oct; 37(10): 1155-1206 Contraindications for Transplant

• Fixed pulmonary hypertension – PVR > 6 woods units • Cirrhosis • Irreversible renal failure • Active smoking, alcohol or drug use • Noncompliance or inadequate social supports • BMI < 19 or > 35 Relative Contraindications for Transplant

• Age • Peripheral vascular disease • Neuropathy • with end-organ damage – proliferative retinopathy • Severe emphysema • Active infection • Malignancy (unless 5 years remission) • Recent PE or stroke • Active peptic ulcer disease Selection Committee

• Surgery • Cardiology • Coordinators • Social Work • Psychiatry • Dietician • Financial Coordinator • Anesthesia • Perfusion • Infectious Disease • Other specialties Adult and Pediatric Heart Transplants Number of Transplants by Year and Location 6000 Other 5500 North America 5000 Europe 4500 4000 3500 3000 2500 2000

Number of transplants 1500 1000 500 0

NOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry. As 2018 such, the presented data may not mirror the changes in the number of heart transplants performed worldwide. JHLT. 2018 Oct; 37(10): 1155-1206 Heart Transplantation

Limited donor supply – 3,000 / yr Estimated total need: 60-100K / yr

• 1 in 24 to 1 in 50 receives organ • Up to 30% waiting list mortality

The Evidence: Survival in VAD Trials

NEJM 2009;361:2282-85.

HeartMate III LVAS

Mehra MR, Naka Y, et al. NEJM 2016;376:440-50.

Adult Heart Transplants % of Patients Bridged with Mechanical Circulatory Support* (Transplants: January 2005 – December 2016) 60

50

40

30

% % of Patients 20

10

0 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 Year of Transplant

2018 * LVAD, RVAD, TAH, ECMO

JHLT. 2018 Oct; 37(10): 1155-1206 Donor Evaluation

• Age < 55 years • Height and weight match within 30% (20% if female donor to male recipient) • No CAD – angiography if age > 45 years or positive risk factors • Normal LVEF • LV wall thickness < 14 mm • Ischemic time < 4 hours Donor Evaluation

• No history of cancer, active infection, HIV, or Hep C • Intractable VT or high-dose inotropes/pressors • Prospective versus retrospective cross- match Immunosuppression

• Induction, maintenance and rescue • Triple-drug maintenance regimen – steroid, calcineurin-inhibitor, anti- lymphocyte proliferation agent Where are we going? Expanding the Donor Pool

• Marginal donors • Remote donors • DCD donors

Donor preservation techniques

• Perfusion systems in the early days – Associated with bleeding and myocardial edema

• Cold storage prevailed due to simplicity and cost Warm

• Allows a new type of • Living organ transplant • Maintains organs in warn functioning state outside of the body › beat › Lungs breath › Kidneys produce urine › Livers produce bile Transmedics – Organ Care System for heart OCS

• Allows organ assessment – HR – Aortic pressure – Coronary blood flow – a/v lactate

Advantages of Ex Vivo Perfusion

• Extend the safe out of body time • Expand the donor pool • Remove the urgency of travel • Removes the urgency of the explant • Allows evaluation of the donor organ prior to transplant • Delivery of pharmaceutic agents that support reparative processes in ischemic myocardium • Potentially allows for angiographic assessment Lancet 2015; 385: 2577–84 Marginal Donors

• Is a marginal donor preferable to bridging mechanical support? • Is a marginal donor preferable to a prolonged wait on an LVAD. • Can warm preservation allow us to use marginal hearts more safely? EXPAND Heart Trial

International Trial to Evaluate the Safety & Effectiveness of The Portable Organ Care System (OCS) Heart For Recruiting, Preserving & Assessing Expanded Criteria Donor Hearts for Transplantation (EXPAND Heart Trial).

Design: Prospective, pivotal, international single-arm trial 72 MGH/29May2016/Tx CF and Lactate Trend

Confidential © EXPAND Results

• 93 eligible donor hearts with a mean UNOS match run of 66 declines were assessed on OCS Heart. • Donor categories were as follows: – x-clamp time > 4 hours (37%) – LVH (23%) – EF 40-50% (23%) – downtime > 20 minutes (28%) – older age (13%) EXPAND Results

• 75 of the 93 donor hearts were successfully transplanted resulting in a utilization rate of 81%. • Mean OCS perfusion time was 6.35 hours. • Incidence of severe LV or RV PGD at 24 hours was 10.7% • 30-day and 6-month survival were 94.7% and 88% respectively. Donation after circulatory death (DCD)

• Successfully increased abdominal organ donor pool • Successfully used in • Used in first human transplants • Encouraging result in animals Challenges of DCD Cardiac Donors

• obligatory hypoxic cardiac arrest and warm ischemic standoff period before organ procurement. • Subsequent reperfusion initiates complex cascade of events that generate intracellular calcium overload, reactive oxygen species, and an inflammatory response that result in myocardial injury. Can warm perfusion systems be utilized to assess DCD organs? DCD Experience NEOB Research Grant

• Protocol Title: Evaluation of ex vivo perfusion system for cardiac reanimation following procurement after circulatory death. – 6 DCD heart from region 1 – Modified system to assess ventricular function – Assess out ability to recover hearts using strict, clinically oriented acceptance criteria New England Organ Bank Research Grant Donor characteristics

Donor I Donor II Donor III Donor IV Donor V Donor VI

Age (years) 51 28 31 39 36 38 Anoxia Cardiovascular Cardiovascular Anoxia due to Anoxia due to an Cause of Death secondary to ALS Anoxia due to Anoxia due to severe asthma overdose aspiration in ALS Drug Overdose asphyxiation Yes; unknown CPR prior to admission (minutes) No No 25 15 Unknown duration

Time from withdrawal of life support until Declaration of 44 29 17 18 20 15 Death (minutes)

Time from Declaration of Death 8 5 9 10 6 7 until cold Cardioplegia (minutes)

Total warm ischemic time 52 34 26 28 26 22 (minutes)

Heart recovery and 38 39 28 31 24 21 instrumentation (minutes)

Total support on OCS (minutes) 268 315 304 374 263 264

Advancing the field

• Warm ex vivo perfusion can – Preserve donor hearts for extended periods – Assess suitability of marginal hearts • Can we safely expand the donor pool to include DCD donors? – Will perfusion systems prove safe and effective? • Cost effective? Future of Transplantation? Tolerance: An absence of injurious immune responses to an allograft without chronic immunosuppression

Neonatal Tolerance

The Promises Indefinite survival Of Tolerance: No drugs (no related side effects) Immunocompetence (less infections, cancer) No chronic rejection Mixed Chimerism Strategy: Combining Organ and Bone Marrow Transplantation

1. Nonlethal XRT +/or T cell depletion. • Reduces alloreactive clones and makes “room” for stem cell transplant.

2. Hematopoietic stem cell transplantation. • Donor DCs in thymus educate T cell T cell depletion precursors and promote Bone Marrow Tregs. & Kidney 3. Organ transplantation First Human Trial in HLA Mismatched Living Donor Renal Allograft Recipients

Kidney Tx Marrow Tx TI 7Gy steroids Cyclophosphamide CNI

-7 -5 -4 -2 -1 0 1 2 5 12 days 9-14 months

Anti-CD2 mAb

Anti-CD2 mAb Rituximab

89 Mixed Chimerism in Living-Related Kidney Transplant Patients

Volume 358:353-361 January 24, 2008 Number 4 Jenn Searl wearing her 15th Happy Transplantversary Crown

91 Mixed Chimerism for Tolerance

Advantages Disadvantages/Questions

• Robust tolerance • Not applicable to possible cadaveric donors • Human trials • Not effective in proceeding in live sensitized recipients donor kidney • Organ-specific effects? transplant recipients • Brain death effects? “Xenotransplantation is the Future of Transplantation…

and always will be.” Humanize the Pig

Eliminate the Galα1-3Gal antigen to prevent hyperacute rejection

First cloned Galα1-3Gal knock-out miniature swine born November 2002 Historic cardiac xenograft survival

1986-1996

1997-2003

2004-2005 HOURS

DAYS

Expert Rev Clin Immunol. Mar 2010; 6(2): 219–230. WEEKS Results: Graft survival

Mohiuddin MM et al., JTCVS 2014;148:1006 Inactivation of porcine endogenous retrovirus in pigs using CRISPR-Cas9

Church/Yang Laboratories Science 22 Sep 2017 After 50 years of heart transplantation…

• Basic technique of heart transplantation unchanged • Patient results continue to improve but… • Epidemiologically trivial impact on • Marginal donors and DCD hearts are a potential source of additional organs and their suitability for transplantation can be assessed with warm ex-vivo perfusion • Ex vivo perfusion is a potentially disruptive technology that could substantially increase the therapeutic impact of heart transplantation • Tolerance is possible • Xenotransplantation may indeed be the future MGH Heart Transplant Volume 1985- 2018 YTD

60

50

40

30

20 Number of Transplants 10

0 1985 1988 1991 1994 1997 2000 2003 2006 2009 2012 2015 2018

103 Heart Deceased MGH Expected National Donor Graft Survival

1 Month 1 Year 1 Month 1 Year 1 Month 1 Year

Adult % Graft 96 91.57 96.22 91.07 96.36 91.50 Survival

104 MGH Heart Transplant Team Thank you