Cardiac transplantation

heart transplantation

1. Heart transplantation Dr. K V Siva Krishna

2. Topic outline Definition Histrory Indications Recipient selection Donor selection Surgical proceedure Post operative management Immunosuppression Rejection Complications

3. DEFINITION Cardiac transplantation is a therapeutic procedure whereby the heart of a suitable donor is implanted into a recipient

4. Carrel and Guthrie first reported successful heterotopic cardiac transplantation in dogs in 1905 1933 Mann and colleagues at Mayo Clinic reported successful transplantation of the heart into the neck of dogs . Medawar was the first to develop concepts of immunology applicable to transplantation. Lower and Shumway first reported successful experimental orthotopic cardiac transplantation in 1960. Orman Shumway is widely regarded as the father of heart transplantation although the world's first adult human heart transplant was performed by a South African cardiac surgeon, Christiaan Barnard , utilizing the techniques developed and perfected by Shumway and Richard Lower.

5. In 1964, Hardy and colleagues performed the first heart transplant into a human, using a chimpanzee heart. The first human-to-human heart transplant (allograft) was performed in Cape Town, South Africa, by Christiaan Barnard on December 3, 1967. The recipient was Louis Washkansky , a 53-year-old ex-boxer with end-stage ischemic cardiomyopathy

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7. - Three days after the Cape Town operation, Adrian Kantrowitz performed the second human heart transplant in Brooklyn. The recipient was an 18-day-old neonate with Ebstein anomaly, refractory heart failure, and previous aortopulmonary shunt for severe cyanosis

8. Barnard performed the third human heart transplant on Philip Blaiberg , a 46-year-old dental surgeon with refractory heart failure, severe coronary artery disease, and a large left ventricular aneurysm. He became the first long-term survivor, living for 18 months. Norman Shumway performed the fourth heart transplant 4 days later, and this patient died 2 weeks later .

9. By the early 1970s, cardiac transplantation had largely disappeared from clinical practice . The report of Caves and colleagues describing a method of transvenous endomyocardial biopsy was an important clinical advance because it allowed monitoring cardiac allograft rejection on a serial basis

10. DENTON COOLEY AND CARDIAC TRANSPLANTATION

11. Denton Arthur Cooley (born August 22, 1920) is an  American  heart  surgeon  famous for performing the first implantation of a total artificial heart . Cooley had by far the largest experience . DeBakey , Cooley, and Shumway, had treated two dozen patients; of them thirteen were alive in 1970s.

12. In INDIA Collectively, 129 heart transplants have been performed in India since 1994 with 82 in Chennai, 33 at AIIMS and 14 at other centres in India. At KEM Hospital, Mumbai, Dr PK Sen and his team performed the first heart transplant in India in February 1968, months after the first attempt at heart transplant was made by Christiaan N. Barnard in December 1967 at South-Africa. Barnards's patient lived for 18 days while Sen's patient died within 24 hours, this was before immuno -supressing drugs were made

13. The Organ Transplant Bill 1994 was passed in the Indian Parliament in May 1994 which cleared the way for organ harvest from brain-dead patients. Successively , Dr P Venugopal and his team performed the first successful heart transplant on August 3, 1994 . The full extent of the law and notification happened in 1995 after which other centres in India performed the surgery successfully. 

14. Hyderabad first transplant was done in global hospital. 6 heart transplants have been done in NIMS

15. Adult and Pediatric Heart Transplants Number of Transplants by Year NOTE: 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. JHLT. 2014 Oct; 33(10): 996-1008 2015 JHLT. 2015 Oct; 34(10): 1244-1254

16. Adult and Pediatric Heart Transplants Number of Transplants by Year and Location NOTE: 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. JHLT. 2014 Oct; 33(10): 996-1008 2015 JHLT. 2015 Oct; 34(10): 1244-1254

17. DIAGNOSIS IN ADULT HEART TRANSPLANTS ISHLT

18. Registry of the International Society of Heart and Lung Transplantation. J Heart Lung Transplant 2007;26:796–807 cardiac transplantation during childhood aged less than 1 year.

19. Registry of the International Society of Heart and Lung Transplantation. J Heart Lung Transplant 2007;26:796–807 Cardiac transplantation aged from 1 to 10 years

20. Adult and Pediatric Heart Transplants Kaplan-Meier Survival (Transplants: January 1982 – June 2013) N = 112,521 N at risk at 30 years = 16 JHLT. 2014 Oct; 33(10): 996-1008 2015 JHLT. 2015 Oct; 34(10): 1244-1254

21. Adult and Pediatric Heart Transplants Kaplan-Meier Survival by Age Group (Transplants: January 1982 – June 2013) p < 0.0001 JHLT. 2014 Oct; 33(10): 1009-1024 2015 JHLT. 2015 Oct; 34(10): 1244-1254

22. Surviving stars Louis Washkansky  was the first recipient of heart transplant in South Africa by Dr Christian Barnard. He survived the operation and lived for 18 days Tony Huesman  is the world's longest living heart transplant recipient who survived 31 years. He received a heart in 1978 at the age of 20 after viral pneumonia severely weakened his heart. Huesman died on August 10, 2009 of cancer. He was operated at Stanford University under heart transplant pioneer Dr Norman Shumway Elizabeth Craze , now 32 years old, an IT employee working for Facebook in Palo Alto is one of the youngest successful heart transplant recipients in the world who received transplant at the age of two years and 10 months

23. Indications for heart transplantation The ACC/AHA guidelines include the following indications for cardiac transplantation : Refractory cardiogenic shock requiring intra-aortic balloon pump counterpulsation or left ventricular assist device (LVAD); Cardiogenic shock requiring continuous intravenous inotropic therapy (i.e., dobutamine , milrinone , etc.); Peak VO2 (VO2max) less than 10 mL/kg per min ; NYHA class of III or IV despite maximized medical and resynchronization therapy; Recurrent life-threatening left ventricular arrhythmias despite an implantable cardiac defibrillator, antiarrhythmic therapy, or catheter-based ablation; End-stage congenital HF with no evidence of pulmonary hypertension Refractory angina without potential medical or surgical therapeutic options .

24. Severe symptoms, with dyspnea at rest or with minimal exertion ( NYHA class III or IV ); Episodes of fluid retention (pulmonary or systemic congestion, peripheral edema ) or of reduced cardiac output at rest (peripheral hypoperfusion ); Objective evidence of severe cardiac dysfunction (at least one of the following): Left ventricular ejection fraction less than 30%, Pseudonormal or restrictive mitral inflow pattern on Doppler echocardiography, High left and/or right ventricular filling pressure Severely impaired functional capacity demonstrated by one of the following: inability to exercise, 6-minute walk test distance less than 300 m (or less in women or patients who are age 75 and older), or peak oxygen intake less than 12 to 14 mL/kg/min; 4. One or more hospitalizations for HF in the past 6 months. ESC : Features that must be met before consideration for heart transplant which are more specific and include, functional, structural and symptoms parameters:

25. Recipient Evaluation and Selection If patients were selected primarily on the basis of highest expected posttransplant survival and quality of life at 1, 5, and 10 years, transplantation would be recommended For less ill patients whose survival is acceptable with medical or nontransplant surgical therapy Patients closest to death from end-stage heart disease, the associated noncardiac organ dysfunction.

26. Decision making is important why? Supply of organs is inadequate Allocation of a donor heart to a patient with a relatively better prognosis would deprive a more seriously ill patient with a short life expectancy (but preserved noncardiac organ function) the opportunity for transplantation at a time when his or her benefit would still be maximal, and Cardiac transplantation is not curative , is associated with its own chronic morbidity and survival limitation , and should therefore not be offered to patients with intermediate- or long-term survival approaching that of transplantation .

27. Seattle heart failure model calculator

28. Absolute contraindications Systemic illness with a life expectancy 2 y despite HT, including Active or recent solid organ or blood malignancy within 5 y ( eg . leukemia , low-grade neoplasms of prostate with persistently elevated prostate-specific antigen) AIDS with frequent opportunistic infections Systemic lupus erythematosus , sarcoid , or amyloidosis that has multisystem involvement and is still active Irreversible renal or hepatic dysfunction in patients considered for only HT Significant obstructive pulmonary disease ( FEV1 1 L/min ) Fixed pulmonary hypertension Pulmonary artery systolic pressure 60 mm Hg Mean transpulmonary gradient 15 mm Hg Pulmonary vascular resistance 6 Wood units

29. Donor selection Brain death is a hostile environment for the donor heart that undoubtedly contributes to the occurrence of primary graft failure (PGF) after HT.

30. Extended Criteria (Marginal) Donor Heart

31. 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

32. Matching Donor and Recipient Because ischemic time during cardiac transplantation is crucial, donor recipient matching is based primarily not on HLA typing but on the severity of illness, ABO blood type (match or compatible), response to PRA, donor weight to recipient ratio (must be 75% to 125%), geographic location relative to donor, and length of time at current status. In the renal transplant population, prospective lymphocyte cross- matching is routinely performed; however, prospective donor recipient cross-matching is often not feasible for thoracic transplantation

33. Recipient management The degree of sensitization of cardiac transplant recipients is most commonly assessed by testing the sera of prospective recipients against a panel of lymphocytes known as the panel-reactive antibody (PRA ) screen. A PRA higher than 10% is considered to represent sensitization. PRA determination using lymphocyte cytotoxic antibody screening (complement-dependent cytotoxicity) is less accurate in the detection of truly sensitized patients than screening using flow cytometry .

34. Elevated PRA titres are found more frequently in patients with a history of multiple transfusions and previous allograft transplant, and in multiparous women . Elevated PRA has more recently been identified in patients with VADs The mechanism responsible for the increased production of HLA antibodies in VAD patients is likely multifactorial and includes T cell deregulation with prominent B cell activation . Recipients of VADs who do not receive blood products may become fully sensitized because of an immunological reaction at the blood-VAD interface

35. A commonly reported regimen consists of monthly treatment with IV Ig at a dose of 2 g/kg. Plasmapheresis has been used to reduce HLA antibody alloreactivity with variable success.

36. Oversizing of a donor heart can occur ( 1) in pediatric HT when the size of the donor heart for a smaller recipient is misjudged ; ( 2) when the native heart disease does not result in cardiomegaly and a larger donor heart is implanted; or (3) after multiple previous operations resulting in rigidity of the mediastinum despite maneuvers such as opening the left side of the pericardium to allow the donor heart to protrude into the left pleural space. These situations may be associated with inability to close the chest without hemodynamically important cardiac compression. Severe undersizing is also an important issue, since a small donor heart may be unable to support the circulation of a much larger recipient. Making the determination of the adequacy of the size of a donor for a specific recipient and judgment is required. Donor-Recipient Size Matching

37. Determination of donor/recipient size match is complicated by the poor relationship between echocardiographic adult heart size and body weight. As a general rule, the donor weight should be within 30% of the recipient weight for adults. However , in non-urgent recipients survival was not adversely affected by undersizing of donor hearts up to a donor to recipient body weight ratio of 0.8. In contrast, survival was inferior in UNOS status 1 recipients, if they received an undersized heart presumably due to a smaller cardiac reserve.

38. Orthotopic implantation is the most common – it involves complete explantation of the native heart . Biatrial anastomosis: Most common because the ischemic time is shorter. Complications include atrial dysfunction due to size mismatch of atrial remnants and arrhythmia (sinus node dysfunction, bradyarrhythmias , and AV conduction disturbances) that necessitate PPM implantation in 10-20% of patients. Bicaval anastomosis: Decreases incidence of arrhythmias, the need for a pacemaker, and risk for mitral or tricuspid regurgitation. However narrowing of the SVC and IVC make biopsy surveillance difficult and ischemic times can be prolonged.

39. Surgical Transplantation Techniques Heart transplantation Orthotropic heart transplantation Heterotpic heart transplantation Techniques Bicaval approach Bi atrial approach

40. It is important to carefully plan the entire operation to attempt to limit the donor ischemic time to less than 6 hours and preferably less than 4 hours. Ischemic times should also be limited to around 4 hours or less in situations where the donor heart is marginal (older donor) as well as in recipients with increased pulmonary vascular resistance.

41. Both the bicaval and the biatrial technique can be safely performed with excellent long-term outcomes in patients with endstage heart failure. Numerous studies have been performed comparing both these techniques with varied results. The bicaval technique preserves normal atrial morphology , sinus node function , and valvular function .

42. As a result, it has consistently been associated with a decreased incidence of atrial arrhythmias and the need for pacemaker implantation . However , potential disadvantages include an increased ischemic time and the possibility of narrowing of the caval anastomosis .

43. Standard median sternotomy is Performed The vena cavae are also cannulated (preferably with right-angled metal tip cannulas) as distally as possible

44. Recipient cardiectomy the aorta is cross-clamped cavo -atrial junction incision is ideally made : medially through the ostium of the coronary sinus and laterally through the floor of the fossa ovalis cuff of posterior left atrial tissue BIATRIAL TECHNIQUE The SVC is doubly ligated and the right atrium is opened from the lateral IVC toward the right atrial appendage, to avoid the sinus node

45. Donor heart The left atrial cuff Connecting incisions between each of the 4 pulmonary veins The superior vena caval cuff is trimmed at the level of the azygous vein opening and more if adequate recipient cuff is present

46. Orthotopic heart transplantation: bicaval anastomosis technique Suturing the LA Superior and inferior vena caval anastomosis Pulmonary artery and aortic anastomosis.

47. Orthotopic heart transplantation: biatrial anastomosis technique The right atrial anastomosis is initiated at the superior end of the atrial incision. A long 3-0 Prolene suture is used and the suture ends are carried both inferiorly and superiorly to first complete the septal anastomosis, and then they are joined at the lateral wall of the septum.

48. Completed orthotopic heart transplantation Reperfusion Look for LA anastomotic site bleed RA RV site Inotropic support Vasodilators

49. CPB separation May develop bradyarrythmias Require direct acting sympathomimetics , pacing Most grafts recover normal ventricular function Dysfunction secondary to ischemia Concern with early recognition of right ventricular failure RV failure PVR > 4 Woods units with little or no reversibility preop Low CO with elevated CVP (> 15) and elevated PAP (> 40). PCWP may be low.

50. The most common reason for failure to wean a heart transplant recipient from cardiopulmonary bypass is right-sided heart failure, evidenced by a low cardiac output despite a rising central venous pressure.

51. Heterotopic heart transplantation Heterotopic heart transplantation involves a donor heart being connected in parallel with the recipient heart. The end result involves four surgical anastomoses: at the levels of the right atria , left atria, aortas, and pulmonary trunks.

52. Advantages to the heterotopic technique compared with the traditional orthotopic approach. The native heart basically functions as an “assist device ” and usually can maintain circulation during: I. recovery of donor heart function from ischemia sustained during transplantation. 2. severe rejection episodes. 3 . the period of adaptation of a small donor heart to the demands of the circulation. 4.the period of adaptation during which the PVR decreases after transplantation and 5. a period of chronic rejection, while the patients awaits retransplantation .

53. There are, however, a few distinct disadvantages inherent in heterotopic transplantation that cannot be ignored. These include: I. the continuing risk of embolic episodes originating from thrombi in the poorly contracting native left ventricle ; 2 . angina , which may be secondary to persistent ischemia in the native myocardium, and 3 . functionally significant right lower lobe atelectasis secondary to the position of the heterotopic heart . This can be a source of persistent pulmonary dysfunction and recurrent pneumonia.

54. Post transplant physiology Cardiac denervation is an inevitable consequence : a denervated donor heart.   The atrial remnant of the recipient remains innervated, but no impulses will cross the suture line. As a result, the donor atrium is responsible for heart rate generation. The transplanted heart has a higher intrinsic rate and reduced rate variability. Resting heart rates range from 90 to 110 beats per minute. Normal responses to changes in position, e.g. orthostatic changes, are lost as are the variations in response to stimuli such as the Valsalva manoeuvre, carotid sinus massage.

55. Intrinsic functions such as cardiac impulse formation and conduction are intact. The Frank-Starling mechanism is also intact In the innervated heart, the normal acute response to a sudden reduction in intravascular volume is a simultaneous increase in both heart rate and contractility. In the denervated heart , however, the initial response via the Frank-Starling mechanism is an increase in stroke volume dependent on an adequate left ventricular end diastolic volume . The increased contractility secondary to heart rate is a secondary effect and is dependent on circulating catecholamines . The transplanted heart is, therefore, critically preload dependent; higher filling pressures are needed .

56. Early Post-operative Care of the Heart Transplant Recipient

57. Peri -operative and Post-operative Monitoring: Recommendations on the Post-operative Monitoring of Heart Transplant Recipients Class I: Peri -operative monitoring of heart transplant recipients should include (1) continuous ECG monitoring ; (2) postoperative 12-lead ECG; (3) invasive arterial pressure monitoring ; (4) direct measurement of RAP or CVP ; ( 5) measurement of left atrial or pulmonary artery wedge pressure (PAWP ); (6) intermittent measurement of CO ; ( 7) continuous measurement of arterial oxygen saturation ; ( 8) intra-operative TEE ; (9) continuous assessment of urinary output . Level of Evidence: C.

58. Hemodynamic Management Cardiac function of the donor heart is usually good but is subject to influences of total denervation and consequences of myocardial ischemia attending explant and transplant. Cardiac denervation may temporarily lower heart rate; consequently, a chronotropic catecholamine agent may be indicated. Isoproterenol in doses of 0.01 to 0.1 μg · kg−1 · min−1 or atrial pacing can be used to maintain an appropriate heart rate for patient age and size

59. Acute distention and failure of the right ventricle resulting from excessive right ventricular afterload is occasionally observed , most commonly in the presence of preexisting recipient pulmonary hypertension or reactive pulmonary vasoconstriction from CPB or protamine administration. Various agents may dilate pulmonary vasculature, but the most effective combination appears to be milrinone at 0.3 to 1 μg · kg−1 · min−1 and nitric oxide. Rarely , right ventricular mechanical support is required.

60. The frequency and severity of RV dysfunction after HT is variable and may be anticipated in patients with risk factors such as Elevated pulmonary vascular resistance (PVR), Excessive bleeding , Pulmonary edema , Poor donor heart preservation before implant , poor RV protection during allograft implantation, Ischemia from air embolization into the right coronary artery, or Significant donor/recipient size mismatch.

61. Even heart allografts that display excellent early function typically experience a functional decline over the first 12 postoperative hours . This decrease in function is believed to be due to the effects of ischemia and reperfusion and myocardial edema , which result in both systolic and diastolic dysfunction.

62. Reduced myocardial contractility is frequently seen after HT as a result of donor organ trauma, preservation and ischemia , catecholamine depletion, and donor brain death . In addition , myofibrillar degeneration can result from the sympathetic storm accompaning brain herniation

63. Infusion of one or more inotropes in the early post-operative period usually provides the hemodynamic support needed in the first few post-operative days as the heart allograft recovers. These agents are usually weaned over the first post-operative week.

64. Primary graft failure after HT is the presence of severe mechanical dysfunction without obvious anatomic ( surgical) or immunologic causes such as hyperacute rejection. Primary graft failure has been variably defined in the literature as heart allograft dysfunction requiring 2 or more inotropes , or the need for mechanical circulatory support, either with an IABP or a VAD within 24 hours of HT. The true prevalence, therefore, depends upon the criteria used for diagnosis, but estimates range from approximately 1.4% to 30.7%.82, 83, 96-100 It is important to recognize that PGF can result in RV, LV, or biventricular failure. Primary Graft Failure and Right Ventricular Dysfunction.

65. Isolated RV failure is more common than biventricular failure . Cardinal features include an elevated RAP > 20 mm Hg , left atrial pressure < 10 mm Hg, with decreasing CO and high pulmonary artery (PA) pressures, and a falling mean arterial pressure, or normal PA pressures with falling CO.

66. The pathophysiology that underlies PGF is generally multifactorial . It includes recipient characteristics such as pulmonary arterial hypertension and increased PVR, and prior MCS, donor characteristics and factors such as prolonged donor ischemia time, poor organ preservation, and development of reactive oxygen species.

67. Pharmacologic Management of Primary Graft Failure and Right Ventricular Dysfunction Intravenous Vasoactive Medications Class I: 1 . Continuous infusion of an inotropic agent should be used to maintain hemodynamic stability post-operatively. Inotropes should be weaned as tolerated over the first 3 to 5 days. The lowest effective dose should be used. Level of Evidence: C. 2. The following therapies are suggested: a . isoproterenol 1 to 10 μg /min OR b . dobutamine 1 to 10 μ g/kg/min ± dopamine 1 to 10 μ g/kg/min OR c . isoproterenol 1 to 10 μg/min ± dopamine 1 to 10 μ g/kg/min OR d . milrinone 0.375 to 0.75 μ g/kg/min Level of Evidence: C.

68. 3. Continuous infusion of α-adrenergic agonists including phenylepherine , norepinepherine or epinephrine can be used to maintain adequate mean arterial pressure. Level of Evidence: C. 4. Low dose vasopressin (0.03-0.1 U/min) or methylene blue can be added to α-agonist for vasodilatory shock. Level of Evidence: B.

69. Pulmonary Vasodilators Prostaglandin E1 Prostanoids Prostacyclin( pg I2) Inhaled Nitrous oxide Sildenafil (PDE inh )

70. Pericardial Effusion The development of pericardial effusion has been shown to occur in more than 20% of HT recipients. It is uncommon for pericardial effusions to progress to cardiac tamponade .

71. Echocardiography is important for recognition and timely return to the operating room for exploration and evacuation of the hematoma to improve RV mechanics and function. Although early reports identified an association between acute heart allograft rejection and the development or rapid increase of post-operative pericardial effusions, this finding was not confirmed in newer retrospective studies.

72. The three factors that predicted the development of post-operative pericardial effusion were absence of a previous cardiac surgery , the intra-operative use of aminocaproic acid, and lower recipient weight.

73. Three situations require specific combinations of immunosuppressive therapies : ( 1) initial high-dose immunosuppression to facilitate graft acceptance, minimize the chance of early rejection, and potentially favour induction of tolerance ; ( 2) maintenance therapy for chronic acceptance of the allograft; and ( 3) augmented immunosuppression to reverse episodes of acute rejection. Immunosuppression

74. Induction therapy generally includes one of two approaches: 1 . Daclizumab or basiliximab , which block IL-2 receptors 2 . Antithymocyte globulin or OKT3 , which targets the T-cell receptor and causes it to be removed from the cell surface or induces destruction of the entire cell through multiple mechanism The rationale of induction therapy is to provide more intensive immunosuppression at the time when the alloimmune response is most intense. Although induction therapy is used by approximately one-half of transplant programs, a survival benefit attendant on its use has not been clearly established.

75. Maintenance immunosuppression Three main group of drugs 1. steroids 2. calcineurin inhibitors 3. antiproliferative drugs

76. Hirsutism , gingival hyperplasia, and hyperlipidemia are more frequent with cyclosporine, and diabetes and neuropathy are more frequent with tacrolimus

77. TICTAC trial

78. Plasmapheresis Plasmapheresis involves removing blood from the patient, separating plasma by centrifugation or membrane filtration, and reconstituting the remaining blood to the original volume with fresh plasma or 5% albumin . Immunoadsorption Whereas plasmapheresis is a passive process in which immunoglobulins . pass through the filtration membranes with the removed plasma, immunoadsorption involves removing specific antibodies using columns containing immunoadsorbents that specifically bind to immunoglobulins .

79. Photopheresis Photopheresis is an immunomodulatory therapy based on leukapheresis .

80. Total Lymphoid Irradiation Total lymphoid irradiation (TLI) is low-dose radiotherapy that targets lymphoid tissues, including the cervical, axillary, mediastinal , periaortic , and iliofemoral lymph nodes, thymus, and spleen. Nonlymphoid tissue is shielded during treatment Both T cells and B cells are susceptible to radiation injury.

81. Rejection Rejection involves cell- or antibody-mediated cardiac injury resulting from recognition of the cardiac allograft as non-self . Hyper acute Three types Acute Chronic Cellular rejection Humoral rejection

82. Hyperacute rejection results when an abrupt loss of allograft function occurs within minutes to hours after circulation is reestablished in the donor heart and is rare in modern-day transplantation . Mediated by preexisting antibodies to allogeneic antigens on the vascular endothelial cells of the donor organ. Fix complement thrombosis, graft failure.

83. Acute cellular rejection or cell-mediated rejection is a mononuclear inflammatory response, predominantly lymphocytic, directed against the donor heart; It is most common from the first week to several years after transplantation, and it occurs in up to 40% of patients during the first year after surgery.

84. The key event in both the initiation and the coordination of the rejection response is T cell activation, moderated by interleukin-2, a cytokine. Interleukin-2 is produced by CD4 + cells and to a lesser extent by CD8+ cells and exerts both an autocrine and a paracrine response . The endomyocardial biopsy remains the gold standard for the diagnosis of acute rejection.

85. Grading of acute cellular rejection.

86. Risk factors for early rejection include younger recipient age, female sex, female donor, positive cytomegalovirus serologic test results , prior infections, black recipient race, and number of HLA mismatches. Risk factors for rejection

87. Other Diagnostic Modalities Although electrocardiographic analysis, cytoimmunologic monitoring, and a variety of radionuclide techniques have been investigated, echocardiography is the primary modality (other than endomyocardial biopsy) routinely used for rejection surveillance . When acute depression of systolic function ( ejection fraction < 50% ) is observed without another clearly identified cause, acute cellular or humoral rejection should be assumed to be present and appropriately treated, with or without confirmation from endomyocardial biopsy.

88. Identifying a Rejection Episode: A major part of care after cardiac transplantation is directed toward identifying rejection. Endomyocardial biopsy remains the most important method of identification and, along with echocardiographic evaluation , is generally performed every 7 days for the first 4 to 6 postoperative weeks. Biopsy frequency is gradually reduced to every 3 to 4 months . Subltle symptoms that include unexplained fever , joint pain , personality change, and any symptom that can result from cardiac failure are an indication for emergency endomyocardial biopsy and immediate institution of therapy if results are positive.

89. Mild rejection does not require specific intervention. Moderate rejection usually requires some degree of intensification of immunosuppression , which generally includes an oral or intravenous bolus of corticosteroid, and an increase in regular therapies. Any rejection with haemodynamic compromise requires haemodynamic support commensurate with the clinical presentation, and aggressive intensification of immunosuppression.

90. 1 to 8 pulses of intra venous methylprednisolone in doses of 10 – 20 mg/kg each. Persistent rejection may need biological immune modulators such as ATG or anti CD3 monoclonal antibodies( OKT3 ). Reccurent refractory episodes may respond to tacrolimus (0.1mg /kg /day).

91. Antibody-mediated rejection is a serious complication after heart transplantation and is manifested as “graft dysfunction” or hemodynamic abnormalities in the absence of cellular rejection on biops Patients at greatest risk for antibody-mediated rejection are women and patients with a high PRA level or a positive crossmatch . It is estimated that significant antibody-mediated rejection occurs in about 7% of patients, but the rate may be as high as 20 %.

92. Immunofluorescence studies are currently the primary modality for identifying fibrinogen, IgG , IgM , and complement components in the endomyocardial biopsy,H2 which indicates humoral rejection.

93. Chronic rejection , or late graft failure, is an irreversible gradual deterioration of graft function that occurs in many allografts months to years after transplantation The current concept suggests that donor heart dysfunction in the chronic stages of maintenance immunosuppression is either related to chronic rejection mediated by antibodies, or a result of progressive graft loss from ischemia.

94. Complications Infection Infections cause approximately 20% of deaths within the first year after transplantation and continue to be a common contributing factor in morbidity and mortality throughout the recipient’s life. The most common infections in the first month after surgery are nosocomial bacterial and fungal infections related to mechanical ventilation , catheters, and the surgical site

95. Mortality is highest for fungal infections, followed by protozoal , bacterial, and viral infections. Aspergillosis and candidiasis are the most common fungal infections after heart transplantation. Viral infections, especially those due to cytomegalovirus, can enhance immunosuppression, potentially resulting in additional opportunistic infections. Pneumocystis jirovecii , and herpes simplex virus infections and oral candidiasis, to be used during the first 6 to 12 months after transplantation. Prophylactic intravenous ganciclovir or oral valganciclovir generally is given for variable periods in cytomegalovirus- seronegative recipients of a transplant from a cytomegalovirus-positive donor.

96. Medical Complications and Comorbid Conditions.

97. New onset diabetes Glucocorticoids Calcineurin inhibitors Insulin resistance Increased BMI African Americans Patient survival and graft survival, may be adversely affected Renal Insufficiency

98. Hypertension The excess risk of hypertension is related primarily to the use of Calcineurin inhibitors because of both direct effects of the drugs on the kidney and the associated renal insufficiency that also is highly prevalent . The incidence of hypertension may be lower with tacrolimus than with cyclosporine Post-transplantation hypertension is difficult to control and often requires a combination of several antihypertensive agents . . Hyperlipidemia Typically, total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides increase by 3 months after transplantation and then generally fall somewhat after the first year . Cyclosporine increases serum LDL cholesterol and binds to the LDL receptor, decreasing its availability to absorb cholesterol from the bloodstream.

99. Malignancy Neoplastic disorders after cardiac transplantation arise from three major causes: preexisting malignancies, transmission of malignancy from donor to recipient, and de novo malignancy arising after transplantation . Tumors most likely to recur in heart transplant recipients are carcinoma of the lung, lymphoma, skin cancer, and carcinoma of the bladder The incidence of de novo recipient malignancy is approximately 100 times that of the non–age-controlled general population.

100. The basic options for treatment of PTLPD reduction of immunosuppression, surgical extirpation, (3) chemotherapy, ( 4) antivirals, ( 5) anti–B-cell antibodies,and ( 6) cell-based therapies

101. Cardiac allograft vasculopathy : annual incidence rate of 5% to 10 %. CAV is detectable by angiography in 8% of survivors within the first year, in 32% within the first 5 years, and in 43% within the first 8 years after HTx . Severe CAV is positively correlated with persistent inflammation and a higher degree of HLA mismatch.

102. In contrast with eccentric lesions seen in atheromatous disease, CAV results from neointimal proliferation of vascular smooth muscle cells, so that it is a generalized process. Characterized by concentric narrowing that affects the entire length of the coronary tree, from the epicardial to the intramyocardial segments, leading to rapid tapering, pruning, and obliteration of third-order branch vessels

103. The first clinical manifestation of CAV may be myocardial ischemia and infarction, heart failure, ventricular arrhythmia,or sudden death . Angina is rare because of denervation of the heart.

104. Pathophysiology is multi factorial

105. Invasive Detection of CAV Intravascular Ultrasound Intravascular ultrasound (IVUS) is the most sensitive tool for the diagnosis of CAV. IVUS allows a reproducible view of both actual lumen diameter and the appearance and thickness of the intima and media Rapidly progressive CAV , defined as an increase of 0.5 mm in maximal intimal thickness within the first year after HTx , is associated with a significantly increased risk of all-cause death, myocardial infarction, and the subsequent development of angiographically severe CAV.

106. Coronary Angiography Coronary angiography is still the standard for the diagnosis of CAV in most transplant centers , and the angiographic detection of significant epicardial coronary stenoses conveys a poor prognosis. CAV is detectable by angiography in 30% to 50% of HTx survivors after 5 years

107. Noninvasive Screening Dobutamine Stress Echocardiography The sensitivity of dobutamine stress echocardiography compared with coronary angiography is 80 %. When intimal thickening by intravascular ultrasound is taken as the “gold standard,” dobutamine stress echocardiography shows specificities of up to 88%.63

108. Single-Photon Emission CT Annual myocardial single-photon emission CT (SPECT) has a high negative predictive value and appears to be well suited to screening for significant CAV. Multidetector CT MDCT with adaptive multisegment reconstruction has a sensitivity and specificity of 86% and 99%, respectively

109. Biomarkers and Gene Profiling Elevated C-reactive protein concentrations are associated with progression of CAV , Whereas persistently elevated levels of troponin I are associated with a s ignificantly increased risk for subsequent development of CAV . The clinical use of brain natriuretic peptide (BNP) levels as a predictor of survival after HTx remains controversial.

110. Therapeutic Options Statins Vasodilators Endothelial Protection Infection and CAV ( CMV INFECTION) Immunosuppression: mTOR inhibitors

111. The use of everolimus from the time of HTx has shown to preserve the coronary artery lumen at 1 year.

112. Emerging New Strategies for the Prevention or Treatment of CAV Three different strategies for CAV are emerging: (1) inhibition of growth factors, cytokines, and circulating antibodies ; ( 2) cell therapy; and (3) tolerance induction. New therapeutic strategies should be directed against matrix formation Sensitive methods for detecting circulating antibodies and improved therapeutic strategies ( eg:photophoresis ) against these antibodies are currently under investigation.

113. FUTURE PERSPECTIVES Need for improved immunosuppression with less rejection, cardiac allograft vasculopathy and side effects Need for better non-invasive methods to detect acute and chronic rejection Need to focus on improved survival and quality of life Challenges in performing long-term adequately powered multi-centered trials

114. Thank you