Heart Transplantation

Where is world now ?

History Brief

Heart transplantation became a reality in the late 1960s after nearly a half of a century of research in surgical techniques, pathophysiology, and immunology by Drs. Richard Lower and Norman Shumway. Dr. Shumway is regarded as the father of heart transplantation. Dr.Christiaan Bernard, a student of Lower, performed the first heart transplantation in the laboratory on December 3, 1967. Dr. Adrian Kantrowitz performed the first pediatrictransplant on Dec 6, 1967 in New York. He also laid the foundation for formulating the brain death criteria, which later came out of the Ad Hoc Committee of the Harvard Medical School. The early results were quite dismal, and many centers were forced to close their programs. In the late 1970s, survival improved to six years. Major advances in survival should be credited to Dr. Margaret Billingham for standardization of pathological diagnosis of rejection and later development of anti-rejection medicines. In 1983, the U.S. Food and Drug Administration (FDA) approved cyclosporin after its discovery by the Sandoz team. In October 1994, ventricular assist devices (VADs) were approved for supporting patients to transplant (bridge to transplantation [BTT]). In October 2014, Dr. Kumud Dhital of Australia transplanted a heart that was resuscitated after cardiac death of the donor, opening a new door to increasing the number of organs.

Clinicopathological Stages

Stages Description

A Patients at high risk (e.g., with hypertension, atherosclerotic disease, diabetes mellitus, metabolic syndrome, cytotoxin, family history) for HF but without structural heart disease or symptoms of HF

B Patients with structural heart disease (e.g., left ventricular [LV] dysfunction) but without symptoms of HF

C Patients with structural heart disease with prior or current symptoms of HF

D Patients with refractory HF requiring specialized interventions

NYHA CLASS

NYHA Description

I Asymptomatic or symptomatic only at activity levels that would limit normal individuals

II Symptomatic with ordinary exertion (e.g., 2 city blocks or 1 flight of stairs in a faster than usual pace)

III Symptomatic with less than ordinary exertion (e.g., less than 2 city blocks or 1 flight of stairs)

IV Symptomatic at rest

Parameters Systolic (HFREF) Diastolic (HFpEF)

History

Coronary artery disease +++ ++

Hypertension ++ ++++

Diabetes ++ ++

Valvular heart disease ++++ +

Paroxysmal dyspnea ++ +++

Physical Examination

Cardiomegaly +++ +

Soft heart sounds ++++ +

S 3 gallop +++ +

S 4 gallop + +++

Hypertension ++ ++++

Mitral regurgitation +++ +

Rales ++ +

Edema +++ +

Jugular venous distention +++ +

Chest Radiograph

Cardiomegaly +++ +

Pulmonary congestion +++ +++

Electrocardiogram

Left ventricular hypertrophy ++ ++++

Q waves ++ +

Low voltage +++ -

Echocardiogram

Left ventricular hypertrophy ++ ++++

Left ventricular dilation ++ -

Left atrial enlargement ++ ++

Reduced ejection fraction ++++ -

History of Cardiac Transplant

1905- Alexis Carrel & Charles Guthrie -First heterotopiccanine heart TX

1930-Frank Mann- heterotopic heart transplantation atMyo clinic

1946- unsuccessful attempts in the inguinal region, VladimirDemikhov of the Soviet Union successfully implanted thefirst intrathoracic heterotopic heart allograft.

1964-The first human cardiac TX - a chimpanzee xenograftperformed at the University of Mississippi by James Hardy

1967-South African Christian Barnard -first human-to-human heart transplant

Cardiac transplant in INDIA

Organ transplantation act – 1994

Heart transplant program - 3rd August 1994 at AIIMS,New Delhi.

So far only about 70 heart transplants have beenconducted across the country, out of which 26 have beenperformed at the All India Institute of Medical Sciencesalone.

The cost of heart transplant surgery in India is anywherebetween 8 lakhs to 10 lakhs and the monthly cost ofimmunosuppressant drugs is 15,000 to 20,000.

Hyderabad first transplant was done in global hospital

3 heart transplants have been done in NIMS

HETEROTOPIC HEART TRANSPLANTATION

The left atrial anastomosis is performed first using3–0 monofilament polypropylene suture, attachingthe donor left atrium to the incision in the recipientleft atriumThe recipient’s SVC is opened with a vertical

incision, and the anastomosis is performedattaching the donor SVC to the recipient SVCThe aortic anastomosis is performed using 4–0

monofilament suture in an end-to-side mannerEither the right or left PA branch is over sewn, with

the other participating in the anastomosis with thedonor PA A prosthetic graft may be required if the donor PA

length is not adequate.

BICAVAL VS STANDARD TECHNIQUE

A biatrial anastomosis results in an abnormally enlarged atrial cavity and distorted atrial geometry, producing atrioventricular (AV) valvularinsufficiency . Additionally, bradyarrhythmias may arise because of the close proximity of the right atrial suture line to the sinus node, resulting in node injury

Yacoub and Banner modified the standard technique described by Lower and Shumway . A bicaval approach preserves the donor atria and combines the standard left atrial anastomosis with a separate bicaval anastomosis

Another approach is total orthotopic heart transplantation. This approach was described by Webb and Neely in 1959 and introduced by Dreyfus and Yacoub in 1991 .

It involves complete recipient atrial excision with complete AV transplantation, in addition to separate

Bicaval and pulmonary venous anastomoses . This technique’s major disadvantages are the additional time required to complete the six anastomoses and the technical challenge of performing the pulmonary vein island anastomoses

Physiology of Transplant

Biatrial connection means less atrial contribution to stroke volume.

Resting heart rate is faster-95 to 110 bpm

acceleration of heart rate is slower during exercise because of denervation

Diurnal changes in blood pressure are abolished

Diastolic dysfunction is very common because the myocardium is stiff from some degree of rejection and possibly from denervation.

Surgery for heart failure • CABG

• Valve replacement

• Left ventricular reconstruction

• Passive cardiac support devices

• Heart transplantation

Heart transplant

• Evaluation of the potential recipient

• The cardiac donor

• Surgical considerations

• Immunosuppression

• Rejection

• Medical complications and comorbid conditions• Malignant Neoplasia• Diabetes• Hypertension • Hyperlipidaemia • Cardiac Allograft Vasculopathy

• Outcomes after Heart Transplantation Survival

• Functional Outcomes

Care of Heart Transplant Patients After Surgery

Short- and long-term management of cardiac transplant patients involves cardiac support, as well as monitoring and treatment of rejection, infection, and malignancies. Organ rejection presents itself as hyperacute, acute cellular or acute antibody-mediated rejection. Hyperacute rejection occurs within minutes to hours due to binding of preformed antibodies to donor antigens leading to complement fixation in vessels and tissue death. Acute cellular rejection is more common in the first six months occurring in 20-40%. It is T cell-mediated against the donor's human leucocyte antigen (HLA). Acute antibody-mediated rejection occurs in about 10% usually due to antibodies driven by T cells to donor vascular antigens.

Care of Heart Transplant Patients After Surgery

This leads to B cell activation and production of plasma cells. It is difficult to diagnose but usually associated with detection of immunoglobulins, complement fragments, CD 68 positive cells, and de novo anti-HLA antibodies. Surveillance endomyocardial biopsies are essential in the first year to detect rejection at the subclinical level before the development of cardiac dysfunction.4 Infants and children have lower rejection rates while adolescents have higher rates. Any symptoms after heart transplant need to be assumed to be due to rejection. There are several adjunct noninvasive measures under investigation based on electrophysiology, magnetic resonance imaging, biochemical markers, and gene expression profiling.

Care of Heart Transplant Patients After Surgery

The introduction of mycophenolate mofetil (MMF), tacrolimus, cyclosporine microemulsion, sirolimus, rapamycin protein inhibitors, new generation monoclonal antibodies ( anti-interleukin-2 receptor antagonists, daclizumab, basilix-imab, alemtuzumab), OKT3, and the depleting polyclonal biologic thymoglobulin has significantly increased the ability of physicians to fight rejection.However, there is a price to pay in the form of increased infections and malignancies. The problem of intimal and smooth muscle proliferation leading to graft vessel disease remains unresolved. Recent advances in therapy have been minimal except for drug minimization protocols leading to reduction of corticosteroid and calcineurin inhibitors. At the same time, the advances in the management of allosensitization are noteworthy. The crossmatch prevents transplanting in the presence of donor-specific antibodies. Panel reactive antibody (PRA) screening is done in all heart transplant candidates, and further evaluation is needed if PRA levels are elevated above 10%.

Care of Heart Transplant Patients After Surgery

• The factors involved leading to sensitization are homograft use in congenital surgery, female sex, prior pregnancies, black race, VAD surface exposure, retransplantation, perioperative blood products usage, and infections. It is diagnosed by measuring PRAs. PRA levels greater than 10% are treated, and aggressive desensitization with plasmapheresis, intravenous immunoglobulin (IVIG), and rituximab is associated with significantly improved survival. IVIG is used to neutralize preformed antibodies before and after transplantation. The effectiveness is variable. Plasmapheresis is fast, short-lived, and can be done immediately before transplantation. Rituximab (anti-CD20) is frequently used and is effective in the long term. Immunoabsorbtion and spelenectomy are rarely used.Therate of infection is very high with these therapies. Because of their immature immune systems, infants can have ABO incompatible organs. The limit of isohemagglutinins titer that makes this possible is not determined.

STICH TRIAL

STICH TRIAL

Surgery for Management of Heart Failure (HF): Guideline Recommendations (ESC-2012)

Kaplan-Meier estimates of death from any cause in patients with moderate to severe MR at baseline assigned to receive medical therapy (MED) alone or MED plus CABG who did or did not undergo mitral valve procedures. MVR, mitral valve repair. (From Deja MA, Grayburn PA, Sun B, et al: Influence of mitral regurgitation repair on survival in the surgical treatment for ischemic heart failure trial. Circulation 125:2639, 2012.)

Surgical ventricular repair

Candidate selection Heart transplantation

Kaplan-Meier cumulative 1-year survival of recipients in the derivation cohort (A) and validation cohort (B) as stratified by three-point increments of risk in the IMPACT score used to predict risk of death for patients undergoing orthotopic heart transplantation. (From Weiss ES, Allen JG, Arnaoutakis GJ, et al: Creation of a quantitative recipient risk index for mortality prediction after cardiac transplantation (IMPACT). Ann Thorac Surg 92:914, 2011.)

Modified from Stewart S, Winters GL, Fishbein MC, et al: Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection. J Heart Lung Transplant 24:1710, 2005.

Modified from Stewart S, Winters GL, Fishbein MC, et al: Revision of the 1990 working formulation for the standardization of nomenclature in the diagnosis of heart rejection by antibody mediation. J Heart Lung Transplant 24:1710, 2005.

Modified from Hertz MI, Aurora P, Christie JD, et al: Registry of the International Society for Heart and Lung Transplantation: a quarter century of thoracic transplantation. J Heart Lung Transplant 27:937, 2008.

• Types of Malignant Neoplasia, with Cumulative Prevalence, Reported after Heart Transplantation

Kaplan-Meier survival after report of cardiac allograft Vasculopathy (CAV) within 3 years of transplant and survival in patients without CAV by era.(From Stehlik J, Edwards LB, Kucheryavaya AY, et al: The registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report—2012. J Heart Lung Transplant 31:1052, 2012.)

Kaplan-Meier adult heart transplant survival in first-time recipients by era, showing a 10-year survival rate of at least 50% and an improvement in survival by era. (From Stehlik J, Edwards LB, Kucheryavaya AY, et al: The registry of the International Society for Heart and Lung Transplantation: 29th official adult heart transplant report—2012. J Heart Lung Transplant 31:1052, 2012.)

Future of stage-D heart failure

The most widely used surgical procedure for heart failure is CABG[STICH]

Drop in operative/post op mortality with surgery

VAD

TAVR

Of course heart transplantation in developing heart

Achievement till now

One-year survival after heart transplantation exceeds 80%, with 10-year survival approaching 60% and 20-year survival at about 20%. Survival after retransplantation is about 10% lower. Ten-year survival is highest in patients with adult congenital heart disease, followed by patients with cardiomyopathy, valvular heart disease, ischemia, and retransplantation. Survival also depends on age, gender, and other comorbid factors of recipients and donors. Major causes of early death are primary graft failure; rejection; infection; technical followed later by allograft vasculopathy; lymphomas; other malignancies; and renal, pulmonary, cerebrovascular, and multi-system failures.

Latest news

• The world’s first transplant of a “dead heart” has taken place in Australia, where doctors say that the surgical technique could significantly increase the number of potential donor organs………………….http://www.independent.co.uk/news/science/australian-surgeons-perform-first-successful-dead-heart-transplants-9816729.html

Dedicated readers ,patients and their relatives

http://www.acc.org/latest-in-cardiology/articles/2015/05/26/11/51/heart-transplantation-the-present-and-future?w_nav=CI