Advances in Heart Transplantation and Mechanical Circulatory Support Jeffrey Alexis, MD University of Rochester Medical Center

1st Heart Transplant Dr. Christiaan Barnard South Africa, December 3 1967 Donor was a 25 year old woman who died following an auto accident Recipient was a 55 year old man, lived 18 days, died from pneumonia

Subsequent Rush to do Heart Transplants 1st transplant in US: December 6, 1967 Dr. Adrian Kantrowitz- Maimonides Medical Center in Brooklyn NY 18 day old male received a transplant from 2 day old male, died 6 hours later- acidosis

3rd Heart Transplant: Dr 3rd Heart Transplant: Dr. Christiaan Barnard January 2, 1968, 58 yr old man received a heart from a 24 year old man 1st Adult US Transplant: January 6, 1968, Dr. Norman Shumway, Stanford University, 54 year old man received a heart from a 43 year old man, recipient died 15 days later of multiple systemic complications

100 heart transplants done in 1968 Poor outcomes, 80% of patients died within 1 year Immunosuppression was the major problem 18 transplants done in 1970

Immunosuppressive Drugs in Organ Transplantation Year Therapy 1959 Total Body irradiation 1960-1962 6-Mercaptopurine and azathioprine 1962-1963 Steroids used systemically 1978 Cyclosporine 1989 Tacrolimus 1997 Mycophenolate mofetil 1998 Sirolimus

Immunosuppressive Drugs

Azathioprine Derived from 6-mercaptopurine Inhibits cell cycle; impairs DNA synthesis Developed by Gertrude Elion and George Hitchings who won a share of the 1988 Nobel Prize

Immunosuppressive Drugs

Azathioprine Myelosuppression Leukopenia (White blood cell count) --Side Effects Myelosuppression Leukopenia (White blood cell count) Thrombocytopenia (Platelet count) Anemia (Red blood cell count) Malignancies (cutaneous)

Corticosteroids Anti-inflammatory- inhibit leukotrienes and prostaglandins Immunosuppressive- Impair rate of transcription of genes that encode regulatory cytokines.

Corticosteroids Inhibit white blood cell transmigration through blood vessels Reduce adhesion molecule expression

Corticosteroids Side Effects Diabetes Obesity Cushingoid Features Wound Healing Bone Disorders Colonic perforation Hypertension

Cyclosporine Inhibits Calcineurin pathway- forms complex with cellular protein called immunophilin (Cyclophilin). Inhibits production of IL-2 and other cytokines. Revolutionized solid organ transplantation

Immunosuppressive Drugs

Cyclosporine Side effects Kidney Disease High blood pressure Elevated lipids

Tacrolimus First isolated in 1984 from bacteria Streptomyces tsukubaensis First used as replacement therapy for cyclosporine in liver transplant patients with intractable rejection Inhibits Calcineurin.

Immunosuppressive Drugs

Tacrolimus Side Effects Kidney Disease Neurologic- tremor, headache Glucose intolerance Elevated Potassium

Cellcept- blocks the pathway proliferation of T and B cells Mycophenolate Cellcept- blocks the pathway proliferation of T and B cells Compared with Azathioprine, reduced mortality at 1 yr (6.2% vs. 11.4%; p=0.031), reduction in requirement of treatment for rejection (65.7% vs. 73.7%; p=0.031) Kobashigawa J et al. Transplantation 1998; 507-515 Compared with Azathioprine at 3 yrs, risk of death or repeat transplant reduced (11.8% vs. 18.3%; p<0.01) Eisen HJ et al. J Heart Lung Transplant 2005;24:517-25.

Mycophenolate Side Effects: GI—Nausea, diarrhea Leukopenia

Sirolimus Inhibitor of TOR (Target of Rapamycin), a cytoplasmic enzyme that is critical in connecting signals from T-cell surface to cell nucleus for stimulation of growth and proliferation of lymphocytes Side Effects: Hyperlipidemia Thrombocytopenia (low platelets)

Current State of Heart Transplants 1 year survival 85-90% Median survival 11 years Patients have lived 30 years post transplant 4000 done world wide each year 2000 done in the US each year Long waiting times

Long Waiting Times Number of donors is flat Decreased deaths from motor vehicle accidents and homicides No living related donors

Awaiting Transplant- UNOS Status Status 1A Status 1B Status 2

UNOS Region 9 Long Waiting Times Most transplants are Status 1A Even as Status 1A, wait can be 1 year! Many patients wait for transplant in the hospital

Long Waiting Times, limited number of organs, has led to increase of Mechanical Circulatory Support: Ventricular assist devices (VAD) Total Artificial Heart (TAH) Extracorporeal Membrane Oxygenation (ECMO)

Dr. Cooley used Dr. Debakey’s device without authorization- 40 yr feud History of MCS 1966/67-First Ventricular Assist Device placed by Dr. Michael Debakey- Methodist Hospital in Houston 1969- First TAH placed by Dr. Denton Cooley, at the Texas Heart Institute - device lasted 64 hours Dr. Cooley used Dr. Debakey’s device without authorization- 40 yr feud 1988

History of MCS 1982- First totally implanted artificial heart for permanent use, was implanted- Jarvik 7 to patient Barney Clark who survived 112 days 1988

1988- First continuous flow pump- Hemopump History of MCS 1986 First pneumatic pulsatile LVAD – Dr. Bud Frazier- Heartmate 1000 IP 1988- First continuous flow pump- Hemopump 1988

HeartMate II LVAD

Heartware LVAD

HeartMate3 LVAD

Ventricular Assist Devices No wait time for implant Can be placed as bridge to transplant or as destination therapy Median survival 4 years Heartware device can be used to support the left heart and the right heart

Ventricular Assist Devices While not common, heart function can sometimes improve while a patient is supported with a VAD The VAD can sometimes be removed (this is not common)

ECHO

ECHO

Syncardia TAH

Syncardia TAH

Total Artificial Heart Beneficial when patient has left and right heart disease Beneficial when patient has dangerous arrhythmias- especially ventricular tachycardia

Extracorporeal Membrane Oxygenation

ECMO Can stabilize patients until stable for longer term therapy or heart function recovers

Patient Management Assess Severity of Illness Assess if Sick Enough for Advanced Heart Failure Therapy Assess Candidacy of Advanced HF Therapy Recommend Treatment