The Changing Face of Heart Transplantation

Hari R. Mallidi, MD, FRCSCStanford Cardiothoracic Surgery

7th International Symposium on Stem Cell Therapy & Cardiovascular Innovations

Oldest Record

Legendary Pien Ch’iao

Performed the “Legendary Exchange of Hearts.”

Balance between the spirit and the will

Earlier Experimental Work

Overview of the History of Heart Transplantation

“A parable of regenerative medicine” K. Chien, Nature, 2008

NUMBER OF HEART TRANSPLANTS REPORTED BY YEAR

189 320667

1190

2172

2728

31513381

40204199 4229

4395 4460 4427 4283 42063898

3642 3508 3469 3372 3346 3271 3341 3362 3355

0

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ISHLTNOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry.  As such, the presented data may not mirror the changes in the number of heart transplants performed worldwide

2009

NUMBER OF HEART TRANSPLANTS REPORTED BY YEAR

0

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Other

EuropeNorth America

ISHLTNOTE: This figure includes only the heart transplants that are reported to the ISHLT Transplant Registry.  As such, the presented data may not mirror the changes in the number of heart transplants performed worldwide

2009

Current Challenges

• Changing recipient population• Decreasing donor population• Increasing recipient sensitization

– Desensitization protocols– Acute cellular rejection– Acute humoral rejection

Patient Population

- Better management of advanced heart failure

- Patient population is older and sicker

- Other options to heart transplantation: Mechanical Support

Recipient Selection

Indications• Advanced heart failure

– NYHA Class III or IV– VO2 max ≤12 cc/kg/min (on β-blockers)

and ≤14 cc/kg/min (intolerant β-blockers)

• Incessant VT or high risk of sudden death

• Refractory, severe angina• Congenital heart disease

– Failed Fontan conduit– Failing systemic right ventricle

• Cardiac tumors– Low likelihood of metastasis

Contra-indications (most relative)• Advanced age (>70)• Active systemic infection• Fixed pulmonary hypertension

– PVR > 5 Wood Units or PVRI > 6– TPG > 15-20 mmHg– PAs > 50-60 mmHg or >50% systemic

• Severe renal*, hepatic*, or pulmonary disease

• Obesity (BMI > 30 or >140% IBW)• Severe PVD• Diabetes mellitus

– End-organ damage– Poor glycemic control (HbA1c >7.5)

• Active or recent malignancy• Recent pulmonary infarction• Ongoing substance abuse• Psychosocial:

– Poor compliance– Inadequate social support

Age > 70

• Increasingly older patient population being transplanted

• Oldest transplant currently alive at Stanford was 76yo at the time of his transplant

0

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15

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25

30

35

40

0-9 10-19 20-29 30-39 40-49 50-59 60-69 70+

Recipient Age

% o

f tra

nspl

ants

1982-1991 (N = 21,126)

1992-2001 (N = 40,356)

2002-6/2008 (N = 21,609)

Fixed Pulmonary Hypertension

• High fixed PVR– Might remain a transplant candidate– Will elect to bridge the patient with an LVAD

• Should be an in-patient on inotropic therapy• Not likely to be discharged without LVAD implant

– Follow closely PVR during period of LVAD support

– When/If PVR drops below 2.5 then would reconsider transplant eligibility

Severe non-cardiac organ failure

• Renal failure– Incidence of combined heart-kidney transplant

increasing• 5 Heart-Kidney Transplants in 2009

• Liver failure– Usually a contraindication in acute situation– In young patients with severe 'cardiac' cirrhosis have

done combined transplant

• Pulmonary failure– Combined Heart-Lung Transplant

• Average 5-10 Heart-Lung Transplants per year at Stanford

Obesity (BMI > 30 or > 140% IBW)

• Expanded the acceptance criteria– Accept up to BMI of 35– If BMI > 35

• Consider LVAD implant• Intense exercise and weight loss program• Reconsider transplant eligibility if weight loss

occurs

Diabetes Mellitus

• No longer considered a contraindication unless patient has significant functional limitation

• Poor glycemic control– Hb

A1c >7.5% remains a contraindication

• Patients with poor diabetic control are considered for LVAD therapy

Congenital2%

ReTX2%

Myopathy46%

Misc.3%

Valvular3%

CAD44%

1/1982-6/2008

DIAGNOSIS IN ADULT HEART TRANSPLANTS

203040506070

% o

f Cas

es Myopathy CAD

CAD38%

Valvular2%

Misc.4%

Myopathy51%

ReTX3%

Congenital2%

1/2005-6/2008

ISHLT

2009

Changing Patient Population

Re-transplantation candidates LVAD recipients Multiple previous operations

Complex congenital patients

• New challenges–Sensitized Patients–Surgical challenges–Ethical issues

Sensitized patients

When the magnitude and likelihood of a heightened response can be assertained

When they show >10% panel reactive antibodies (PRA)

More important than high PRA is the presence of donor specific antibodies (DSA) or antibodies directed against the donor heart.

Mehra MR. Curr Opin Cardiol. 2003;18:153-8.

Methods of Assessment

De-sensitization protocols

• All patients with a cPRA > 10%– Goal: Reduce levels of circulating antibodies

• Pre-transplant– IVIG– Rituximab

• Intra-operative– Plasmapheresis

• Post-operative– IVIG– Close monitoring for DSA

ADULT HEART TRANSPLANTS (1989-6/1993) Relative Risk of 15 Year Mortality with 95% Confidence Limits

Recipient Pre-Transplant PRA

0

0.5

1

1.5

2

0 10 20 30

PRA

p = 0.0100

Re

lati

ve

Ris

k o

f 1

5 Y

ea

r M

ort

ali

ty

(N=7,478)2009ISHLT

Matching Donors & Recipients

Matching is based upon:• ABO blood group• Body size compatibility (±

20% body weight)• Antibody screen (PRA)• No HLA prospective

matching done unless high levels of pre-formed antibodies on screening (PRA > 10-20%)

Allocation is determined by:

• Recipient’s priority on waiting list– Status code (1A, 1B, 2)– Time accrued within a status

• Geographic location from donor

Advances in Surgical Technique

Goals:

- Improve surgical technique and preserve cardiac anatomy

- Decrease Ischemic Time

- Improve Myocardial Protection

Organ Preservation

• Decreased organ ischemic time

• Continuous perfusion of organ

• Better organ function

• Recovery of organ function in borderline cases

Biatrial Technique

Bicaval Technique

ADULT HEART TRANSPLANTS (1/2002-6/2007) Relative Risk of 1 Year Mortality with 95% Confidence Limits

Ischemia Time

0

0.5

1

1.5

2

2.5

3

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

Ischemia Time (minutes)

p = 0.0004Re

lati

ve

Ris

k o

f 1

Ye

ar

Mo

rta

lity

2009ISHLT (N=10,705)

POST-TRANSPLANT ISSUES

What to Expect Post-Transplant

• Immunocompromised due to anti-rejection medications– Bacterial, fungal, viral, atypical organisms

• The transplanted heart is denervated– Sinus tachycardia (HR 110-120 may be normal)– May not experience angina– Exercise intolerance, fatigue

• Abnormal ECG• Subtle symptoms (lethargy, nausea) may be the

only signs of rejection or early infection

ADULT HEART TRANSPLANT RECIPIENTS: Relative Incidence of Leading Causes of Death

(Deaths: January 1992 - June 2008)

0

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0-30 Days (N= 3,531)

31 Days – 1Year (N =

3,513)

>1 Year – 3Years (N =

2,716)

>3 Years – 5Years (N =

2,356)

>5 Years – 10Years (N =

5,335 )

>10 Years (N= 3,677)

CAV Acute Rejection

Malignancy (non-Lymph/PTLD) Infection (non-CMV)

Graft Failure

Pe

rce

nta

ge

of

De

ath

s

ISHLT

2009

ADULT HEART TRANSPLANT RECIPIENTS: Cumulative Incidence of Leading Causes of Death

(Transplants: January 1992 - June 2007)

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

10%

0 1 2 3 4 5 6 7 8 9 10

Time (years)

CAV Acute Rejection

Malignancy (non-Lymph/PTLD) Graft Failure

CMV Infection (non-CMV)

Inc

ide

nc

e o

f C

au

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-Sp

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ific

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ath

s

ISHLT

2009

Routine Surveillance

Immunosuppression: General Principles

- Immune reactivity and risk of rejection is highest early (first 6 months) after graft implantation and decreases with time therefore the doses are higher early on.

- Most modern regimens employ low doses of several drugs without overlapping toxicities in preference to higher doses of fewer drugs.

Immunosuppressive Agents

Immunosuppressive Drugs

• Induction therapy with T-cell cytolitic agent– 50% of centers give induction therapy– Multiple agents: OKT3, rATG

• Corticosteroids– Solumedrol 500 mg IV coming off bypass, then 125

mg IV q8h x 3 doses– Prednisone 1 mg/kg divided BID (Day 1-14)– Gradually taper dosage with goal of complete wean

by 6-9 months

Immunosuppression Regimens

Pre-1980’s Typical Graft CAD Renal Sparing

CyclosporinTacrolimus

CyclosporinTacrolimus

Sirolimus

ImuranMMF

ImuranSirolimus MMF

PrednisonePrednisone(month 0-6)

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Cyclosporine Tacrolimus Rapamycin MMF Azathioprine Prednisone

% o

f P

atie

nts

2000 (N = 1,503) 2003 (N = 1,610) July 2007 - June 2008 (N = 1,705)

ADULT HEART RECIPIENTS Maintenance Immunosuppression at Time of 1 Year Follow-up

NOTE: Different patients are analyzed in each time frame.

ISHLT

Analysis is limited to patients who were alive at the time of the follow-up

2009

Rejection

• 30-50% of patients will experience rejection within the 1st year

• Most cases are cellular (T-lymphocyte mediated). Up to 20% are humoral (antibody mediated).

• Presentation:– Asymptomatic (most)– Malaise, fatigue, atrial arrhythmias, pericardial

effusion, low grade fever, GI symptoms– Heart failure, ventricular arrhythmias, and conduction

delays occur late

Identifying Allograft RejectionDisease Progression

Alloimmune activation Cellular invasion

Multiple genes and pathways

Cellular inflamationand myocyte necrosis

Graft Dysfunction

Heart failure andarrhythmias

Diagnostic Indicators

Gene Expression ProfilingImmune Function Assays

Endomyocardial Biopsy(intermediate)

Functional Assessment(late)

Endomyocardial Biopsy

Biopsy Grading (ISHLT)

Old (1990) New (2004) Histology

0 0 No rejection

1A

1R (Mild)Interstitial and/or perivascular lymphocitic infiltrate with up to one focus of myocyte damage

1B

2

3A

3B

4

Biopsy Pathology: AMR

CD28 highlights intravascularMacrophages

C4d staining ofcapillaries

Pham et al., NEJM, Apr 22, 2010

Management of Rejection

• Cellular: dependent upon histology grade and presence of hemodynamic compromise (HDC).– Moderate without HDC: Solumedrol 1 gm IV daily x 3,

augmentation of baseline immunosuppression– Severe or moderate with HDC: As above + antibody

cytolytic therapy– Recurrent or refractory: Total lymphoid irradiation

• Antibody mediated: Plasmapheresis, IVIg, Rituximab, Photopheresis

Cardiac Allograft VasculopathyCoronary Angiogram

Intravascular Ultrasound (IVUS)

Histology(autopsy)

Diagnosis: coronary angiogram, IVUS, Dobutamine stressEchocardiography (DSE), myocardial perfusion imaging (MPS)

1 Mehra et al., JHLT 1995; 2 Rickenbacker et al., Circ 1995

Significance of Intimal Thickening

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30

Ca

rdia

c e

ve

nt

rate

(%

)

MIT > 0.5 MIT ≤ 0.5

Intimal thickening

7/31

1/43

P=0.006

Sudden death, MI, or need forrevascularization

MIT ≤ 0.3mm

MIT > 0.3mm

MIT ≤ 0.3mm

MIT > 0.3mm

Kobashigawa et al, Multicenter IVUS Validay Study, JACC 2005

Effects of MIT change on long-term cardiac outcomes

• 125 Heart Tx patients• 5 centers• Baseline vs 1 year IVUS• 5-year follow-up

DeathGraft lossAcute MICHFNeed for PCI/CABGICD placementCVA, PVDAngiographic CAV

Eisen et al., NEJM 2003; Keogh et al., Circ 2004, Mancini et al., Circ 2003

Effects of PSI on CAV

Rapamycin

Control P<0.01

Patients with established CAVDe novo after OHT

Primary endpoint: death, angioplasty, MI,or >25% increase in catheterization score

Infection

Fishman, NEJM 2007

The Journey Continues

Challenges for the future

• Better define the role of MCS• Improve organ storage / resuscitation• Improved assessment of immunological

risks• Improved rejection surveillance• Improved immunosuppression regimens• Improved prophylaxis against infection and

malignancy

Acknowledgements

Robert C. Robbins, MD

Philip E. Oyer, MD, PhD

Bruce A. Reitz, MD

Sharon A Hunt, MD

Hannah Valantine, MD

Michael Pham, MD, MPH

Francois Haddad, MD

Michael B. Fowler, MD