Cardiomyopathy, End-stage Heart Disease & Transplantation Seoul National University Hospital Department of Thoracic & Cardiovascular Surgery

Cardiomyopathy, End-stage Heart Disease & Transplantation

Seoul National University Hospital

Department of Thoracic & Cardiovascular Surgery

Hypertrophic Cardiomyopathy


Definition• A myocardial disease characterized by left and/or right v

entricular hypertrophy that is usually asymmetric and is associated with microscopic evidence of myocardial fiber disarray. Degree of hypertrophy at any given site can vary substantially & influences clinical manifestations.

• Ventricular septal hypertrophy is the most common type of asymmetric hypertrophy, with midventricular, apical, and other types occurring much less frequently.

• Forms interfering with left ventricular emptying, termed hypertrophic obstructive cardiomyopathy or idiopathic hypertrophic subaortic stenosis, are surgical important and variable subaortic obstruction and is associated with abnormal systolic anterior motion.

• The more commonly occurring nonobstructive forms are not amenable to surgical treatment except for cardiac transplantation.


Historical note• Hallopeau & Liouiville ; Pathologic finding compatible with HOCM in 19

century

• Schmincke ; Pathologic finding in early 20 century

• Davies ; Described family form in 1952

• Brock ; Surgical report for diffuse muscular subaortic stenosis

• Braunwald & Goodwin ; Described respectively idiopathic hypertrophic subaortic stenosis & hypertrophic obstructive cardiomyopathy

• Bigellow ; Simple myotomy using an aortic approach in 1966

• Morrow ; Excision of muscle in 1978

Coronary Flow Reserve

Determinants of microvascular dysfunction• Narrowing of epicardial coronary arteries• Structural changes (ie, vascular remodeling with reduced

lumen to wall ratio) or functional alterations involving neurohumoral factors

• Small coronary arterioles may change their diameter as a result of autonomic innervation

• Several extravascular mechanisms such as impaired diastolic relaxation, compression of the coronary arteries by high left ventricular filling pressures, and increased force of contraction ("milking").


Morphogenesis• Hypertrophic cardiomyopathy is recognized a

heterogenous sarcomere diseases, and mutations have been described in the beta-myosin heavy chain gene (chromosome 14q11-q12), in cardiac troponin-T( chromosome I ), in alpha-tropomyosin ( chromosome 15q2), and in two other chromosomes.

Hypertrophic CardiomyopathyCharacteristics• Ratio of thickness between septum and posterior wall is

1.3 or more in almost HCM.• ASH tends to lessen or disappear with somatic growth

when present in early life in association with congenital heart disease.

• Increased wall thickness is mainly caused by increased fibrous tissue, particularly in the ventricular septum.

• Foci of disarrayed muscle cells are interspersed and also abnormalities in orientation of myofibrils.

• The LV cavity is small and has a S or sigmoid shape in systole.

• Rarely, LV cavity may become dilated in the late stages of HOCM.


Etiology• HCM is a genetically determined disorder of cardiac m

uscle transmitted as an autosomal dominant trait, although nonfamilial cases probably occur as well.

• HCM can present at any age from early infancy to the sixth or seventh decade.

• Echocardiographic studies of patients with HCM, including those with isolated ASH suggest that obstruction is present in only about 20%.

• It is uncertain whether isolated ASH, an asymptomatic disease, develops into obstructive cardiomyopathy.


Natural history• The natural history of HCM is typically variable.• Progression of disease is more rapid in children and

young adults• Symptomatic infants and young children represent the

more severe end of spectrum.• Annual mortality of HCM has ranged 4-6% in children,

and 3-4% in adults.• Sudden cardiac death is common and the risk factors are

young age, syncope, family history of malignancy, myocardial ischemia, sustained VT, degree of outflow obstruction.

Hypertrophic CardiomyopathyMorphology Muscular hypertrophy present in HCM involves the interventricular septum and left ventricle, and id variable in its location and severity• Ventricular septum• Dynamic morphology of septum and mitral valve• Left ventricular free wall• Left ventricular cavity• Histopathology of left ventricle• Left atrium• Mitral valve• Right ventricle • Coronary arteries• Associated lesions


Clinical features & diagnosis• Symptoms ; angina, DOE, syncope, palpitation

• Signs ; late-onset ejection murmur, bifid arterial pulse, palpable left atrial contraction

• Ventricular function ; initial diastolic dysfunction

• EKG ; LV strain, sometimes Q wave, LVH

• Chest radiography ; variable cardiomegaly

• Echocardiography & catheterization


Mitral regurgitation• SAM of the anterior leaflet is a constant features of clas

sic HOCM.• It is likely that severity of mitral regurgitation, magnit

ude of pressure gradient, and degree of prolongation of LV ejection time are determined by time of onset and duration of mitral leaflet-septal contact.

• Mitral regurgitation occurs independent of SAM in about 20% of patients with HOCM.

• It can result from mitral valve prolapse, chordal rupture, anomalous attachment of a papillary muscle, anterior leaflet fibrosis, congenital abnormalities, rheumatic disease, or annular calcification

Systolic Anterior Motion

• The mechanism of SAM is probably multifactorial, most likely, secondary to forward (anterior) displacement of the elongated mitral valve relative to the septum during systole.

• The Ventury effect of the high-velocity stream of blood carries the protruding edge of anterior leaflet toward the aortic annulus in early systole

• SAM is absent in the nonobstructive HCM• SAN can occur in TGA with IVS• SAM may also appear after inserting a rigid mitral anu

loplasty ring

Systolic Anterior MotionProposed Mechanism

A ; Coaptation point( arrow ) is in the body of anterior and posterior leaflets.B & C ; Anterior and basal movement of the residual length of the anterior leaflet with septal contact and failure of leaflet coaptation & subsequent mitral regurgitation

Technique of Operation

Myectomy by aortic approach Adjunts to conventional myectomy• Extended myectomy & reconstruction of

subvalvular mitral apparatus• Plication of anterior leaflet with myectomy• Ventriculotomy with transaortic approach Modified Konno operation Mitral valve replacement


Postoperative care• LAP of 16-18 mmHg required early postoperatively for a

dequate volume• Digitalis, beta-receptor agonist should be avoided• Hypovolemia and nitroglycerin, which can reduce LV vol

ume and exaggerate any residual gradient, should be avoided.

• Atrial fibrillation may be poorly tolerated• This can be best accomplished by use of beta-adrenergic r

eceptor blocking agents ( propranolol ), calcium antagonists ( verapamil, diltiazem ), or amiodarone

Results of Operation• Early death• Time-related survival• Mode of death• Incremental risk factors• Myocardial metabolic changes• Conduction disturbance• Perioperative myocardial infarction• Iatrogenic defects• Postoperative pressure gradients• Mitral regurgitation• Left ventricular aneurysm• Symptomatic status• Left ventricular function

Postoperative Aortic Regurgitation

Causes after operation for HOCM• Small aortic annulus probably by increased oper

ative difficulty & increased retraction & possible injury of aortic valve cusp

• Loss of support of right coronary cusp as a result of excising septal muscle beneath it may result in aortic regurgitation as may altered velocity, direction, and dynamics of the turbulent jet of blood in the outflow tract

Incremental Risk Factors

• Preoperative syncope• Increased NYHA functional class• Documented coronary artery disease• Concomitant procedures• Mitral valve replacement• Development of complete heart block• Outflow tract gradients greater than 15mmHg

were incremental risk factors for late death


Indications for operation• Symptomatic patients after appropriate medical therap

y, pacemaker therapy, or septal ablation and who has LVOT gradient at rest more than 50mmHg

• Symptomatic patients with small gradient at rest but in whom a gradient of 50mmHg or greater on provocation, after ectopic beat, or after cessation of exercise

• Occurrence of atrial fibrillation is also an indication• Less symptomatic patients with severe gradients, with

MR, history of syncope, asymptmatic young patients with gradients more than 100mmHg

Hypertrophic Cardiomyopathy Special situations & controversies

Alterative therapy• Left ventricular-aortic conduit

• Dual-chamber pacing

• Percutaneous transluminal septal myocardial ablation

• Cardioverter-defibrillator

• Cardiac transplantation

Heart Failure

Heart Failure

Definition• A clinical syndrome that represents a complication or c

ommon final pathway of many heart diseases in which defective cardiac filling( diastolic heart failure ) or impaired contraction( systolic heart failure ) or emptying results in the heart’s ability to pump a sufficient amount of blood to support tissue metabolism, or to be able to do so only with elevated filling pressure.

• It is commonly characterized by secondary organ abnormalities in the skeletal muscles( fatigue ), lungs( dyspnea ), and kidneys( salt & fluid retention )

Heart Failure

Pathophysiology• Cardiorenal mechanism

• Hemodynamic mechanisms

• Neurohumoral mechanisms

• Myocardial hypertrophy & ventricular remodeling mechanisms

• Other factors

Mechanisms of Remodeling

• Transition from compensatory hypertrophy to heart failure is related to alterations in cell organization and changes in coronary blood flow to the increased cell mass of the hypertrophied ventricle.

• Alterations in myocyte biology include excitation-contraction coupling, myosin heavy chain or fetal gene expression, beta-adrenergic desensitization.

• Alteration in the extracellular matrix of the myocardium include replacement fibrosis.

• Changes in configuration of the ventricular chamber include dilation, change in shape( increased sphericity), thinning of wall and regurgitation.

Heart Failure

Clinical features & diagnostic criteria• Stage A ; patient at high risk for developing heart

failure but has no structural disorder of the heart

• Stage B ; patient with structural disorder of the heart but has never developed symptoms of heart failure

• Stage C ; patient with past or current symptoms of heart failure associated with underlying structural heart disease

• Stage D ; patient with end-stage disease

Heart FailureNatural history• About 3% of the adult population is treated for heart

failure and occurrence of heart failure increases with age so that 6% to 10% of people older than 65 years have heart failure

• Heart failure accounts about 5-10% of all hospital admissions.

• Heart failure results in nearly 300,000 deaths per year in the United States, 60% sudden.

• Sudden death may be completely unexpected(1/3), a consequence of worsening heart failure(1/3), or a result of progression of heart failure alone(1/3)

Cardiomyopathy

Definition• A cardiac muscle disease process that leads to c

linical myocardial dysfunction• The disease process results in morphologic cha

nges in the heart that are typically classified as (1) dilated cardiomyopathy, (2) hypertrophic cardiomyopathy, (3) restrictive cardiomyopathy, and (4) arrhythmogenic right ventricular dysplasia

Dilated Cardiomyopathy

Definition• A cardiac muscle disease characterized by dilatation of o

ne or both ventricles and impairment of at least systolic function. Dilated cardiomyopathy may be considered the final outcome of pathways produced by a variety of agents of myocardial insult

• These include selenium deficiency , alcohol, smoking, and a variety of viral agents and in some patients, the causative factor may be immune, genetic, or familial.

• In many patients, none of these can be identified, & the condition is termed idiopathic dilated cardiomyopathy


Morphology• Enlargement (increased volume) of ventricles

and, to a lesser extent, the atria• Variable degree of hypertrophy is often present• Extensive interstitial & perivascular fibrosis, occasi

onally calcification, in the ventricular myocardium in microscopic examination

• Myocardial cell degeneration is usually seen• The specific diagnosis of DCM usually cannot be

made by endocardial biopsy

Dilated CardiomyopathyClinical features & diagnosis• DCM frequently is of unknown etiology• Speculation as to possible progression of infective, parti

cularly viral, myocarditis to full-blown dilated cardiomyopathy, particularly frequent in children

• Alcoholism, pregnancy, and systemic hypertension may provide a background for its development

• About 25% of patients have familiar disease (X-linked)• Characterized by impaired systolic function, but in lat

e, decreased left ventricular compliance may develop• Al forms of cardiomyopathy may have a nonspecific pr

odromal phase, lasting weeks or months

Dilated CardiomyopathyNatural history• DCM is a serious disease, and about 80% of patients

are dead within 10 years of its evident onset• The course is variable, with some patients dying within 1

to 2 years and a few having more fulminating course• Cardiac antibodies play a functional role and their remov

al may induce hemodynamic improvement• A few patients with dilated cardiomyopathy recover spon

taneously.• Mode of death is usually chronic cardiac failure, or occasi

onally intractable arrhythmias, and sometimes sudden


Risk factors for death• Marked cardiomegaly

• Cardiac rhythm other than sinus, especially ventricular arrhythmia

• Pulmonary hypertension

• Elevated right atrial pressure

• Thromboembolism in great LV with atrial fibrillation

Restrictive Cardiomyopathy

Definition• A cardiac muscle disease that results in impaired diasto

lic function with loss of compliance

Morphology• Characterized by diffuse ventricular hypertrophy. The

ventricular walls are excessively rigid, resulting in restrictive filling and reduced volume of ventricle with normal or near normal systolic function. Microscopically, fibrosis and hypertrophy of myocytes are usually apparent.

Restrictive Cardiomyopathy

Clinical features & diagnosis• Restrictive cardiomyopathy may be secondary to amyloid infiltration and other process, with or without eosinophilia. In number of cases the etiology is unknown• This condition simulates chronic constrictive pericarditis with severe impairment of compliance• Generally, symptoms are of long duration, & death is delayed for 5 to 20 years after abnormalities of cardiac function and not well defined

Endomyocardial FibroelastosisDefinition• A form of restrictive cardiomyopathy with unknown etio

logy in which the pathologic process is restricted to the endocardium

Morphology• Fibrous endocardial lesions involving primarily the inflo

w portions of right and left ventricles• The outflow of the ventricle is usually spared.• Both ventricles are commonly involved, but 40% purely i

n LV and 10% in RV involvement• A thick layer of hyalinized fibrous tissue, calcification

in endocardium and sparsity of elastic fiber• Possible role of diet in banana, malnutrition, and various

infections as well as an immunologic response

Endomyocardial FibroelastosisClinical features & diagnosis• As progressively increasing endomyocardial fibrosis deve

lops, with consequent restriction of ventricular filling, ventricular end-diastolic pressure elevate as do pulmonary or systemic venous pressure, depending on which ventricle is involved

• Involvement of AV valves then adds valvar regurgitation to the already impaired hemodynamic state

• Endomyocardial fibrosis(or obliterative cardiomyopath ) tends to affect children and young adults with. It occurs primarily in Uganda, Nigeria, and India.

• This type of cardiomyopathy is generally unfavorable, slowly deteriorating course and death within 5 to 10 years, often within 1 to 2 years.

Secondary CardiomyopathiesAssociated with cardiac or systemic disorders

IschemicValvarHypertensiveInflammatory - Myocarditis, Chanas disease, HIVMetabolic – Thyrotoxicosis, Hypothyroidism, Storage diseasesSystemic diseases - Systemic lupus erthematosus, SarcoidosisMuscular dystrophies - Duchenne’s, Becker-typeNeuromuscular disorders - Friedreich’s ataxiaSensitivity and toxic reactions – Alcohol, Radiation, AnthracyclinesPeripartum (pregnancy)

Treatment of Heart Failure

Therapy for Heart Failure

Non-drug therapy

• Dietary sodium restriction

• Exercise training Treatments of no benefit or harm

• Calcium-channel blockers

• Positive inotropic therapy

Heart FailureDrug therapy• Angiotensin-converting enzyme inhibitors, ACE1 Enalpril 10mg bid• Angiotensin-receptor blocker, RBs Losartan 50mg, captopril• Beta-blocker ; Carvedilol, metoprolol, bisoprolol• Aldosterone receptor-blocker Spironolactone 25~50mg/day• Vasodilator ; Hydralazine & isosorbide dinitrate• Digoxin• Diuretics• Antiplatelet therapy & anticoagulation

End-Stage Heart Disease

Surgical Options

1. Ventricular assist device

2. Dynamic cardiomyoplasty

3. Ventricular volume reduction

4. Heart transplantation

Treatment of Dilated Ventricle

Options to Reserve Compensatory Mechanism

1. Increase the LV mass (cardiomyoplasty)

2. Decrease the wall tension (vasodilator)

3. Reduce the LV radius (cardioreduction)

Myocardial Infarction

Sequence• Acute & chronic inflammatory reaction after

infarction and myocardial fibrosis

• Ventricular pressure stretches & thins the healing area including ventricular dilation.

• The dilated heart may result in congestive heart failure.

• Ventricular aneurysm may form, further compromising heart function.

Ischemic Cardiomyopathy

Ventricular Reconstruction • Recommended in patients with coronary diseas

e as a treatment for heart failure, angina, and thromboembolic complications or to control ventricular arrhythmias

Technical modifications • Purse-string technique • Endoaneurysmorrhaphy technique • Endoventricular circuloplasty

Volume Reduction Surgery

1. Selection 1) Dilated cardiomyopathy (LVEDD>70mm)

2) Contraindication to transplantation

3) Hemodynamic deterioration waiting

transplantation

2. Exclusion 1) Ischemic cardiomyopathy

2) Cardiac fibrosis

3) Active myocarditis

Heart Reduction Surgery

Cardiac Function after Reduction1. Increases in end-systolic elastance & preload re

cruitable stroke work, and ejection fraction due to decrease in LVEDV with no little change in stroke volume.

2. Decreases in LVEDV and increases in diastolic chamber stiffness.

3. At any ventricular pressure, mass reduction results in a decrease in ventricular wall stress.

(reduction of myocardial afterload, and subendocardial ischemia)

Dor Procedure

Pathophysiology• Relieve ischemia by revascularization • Diminish ventricular volume• Restore the ventricle to more normal geome

try• Further diminishes volume overload

by mitral valve repair when appropriate

Overlapping Ventriculoplasty

• Schema of integrated overlapping ventriculoplasty with PMP

Septal Aneurysm Patch Exclusion

A, Apical aneurysm with significant thinning and aneurysmal involvement of distal septum. B, Pericardial patch sewn to the preserved normal portion of the septum on three sides. C, The patch effectively excludes the aneurysmal portion of the septum

Dor Procedure

Indications• Anteroseptal infarction and dilated left ventricle

(enddiastolic volume index >100mL/m2)• Depressed ejection fraction(even below 20%)• Left ventricular regional asynergy greater than

35%• Symptoms of angina, heart failure, arrhythmias• Inducible ischemia in asymptomatic patients

Dor Procedure

Contraindications• Systolic PA pressure more than 60mmHg

( when not associated with severe MR)• Severe RV dysfunction as assessed by tric

uspid annulus plane systolic excursion• Regional asynergy without dilation of th

e ventricle ( risk of too small a residual ventricle)

Mechanisms of Cardiomyoplasty

• Girdling effect on the left ventricle reduce chronic dilation decrease diastolic strain

• Enhance systolic performance decrease myocardial workload decrease cardiac oxygen consumption improve myocardial efficiency

Cardiac Transplantation

History• 1960 ; R. Lower & N. Sumway

Successful canine orthotopic cardiac transplantation• 1967 ; C. Barnard Successful human orthotopic cardiac transplantation • 1972 ; P. Caves Percutaneous transvenous RV endomyocardial biopsy• 1974 ; M. Billingham Standard grading system for cardiac biopsy• 1979 ; Cyclosporin A in clinical immunosuppresion• 1985 ; L. Bailey Successful infant orthotopic transplantation

Cellular Transplantation

• Cardiomyocyte• Bone marrow cell• Human mesenchymal stem cells(hMSCs)• Mouse embryonic stem cell(ESCs)• Intracoronary or transendocardial transplantat

ion of autologous mononuclear bone marrow cells

• Cellular transplantation by autologous, allogeneic, or xenogeneic cells for cardiac repair

Cellular Xenotransplantation

Cells for cardiac repair• Somatic cells

• Adult stem cells

Bone marrow stem cells

Satellite cells

• Embryonic stem cells

Heart Transplantation

Infants• Hypoplastic left heart syndrome

• Dilated cardiomyopathy

• Aortic stenosis with endocardial fibroelastosis

• Unstable ventricular tachycardia

• Others

Children• Cardiomyopathy, dilated and restrictive

• Single ventricle s/p Fontan procedure

• Complex cardiac anomalies s/p palliative surgery

• Other complex cardiac anomalies s/p corrective procedure

• Retransplantation, TCAD, Rejection, Early graft failure

Indications


Contraindication in pediatric age• Fixed PVRI more than 6 unit/BSA• Fixed TPG more than 15mmHg• Active infection• Severe metabolic disease• Multiple severe congenital anomalies• Advanced multiple organ failure• Active malignancy

Pretransplant Evaluation

Critical determinants• Pulmonary vascular resistance index PVRI (units/square M) = PAP-PAWP(mmHg)

*mmHg= mean pressure. CI(L/min/square M)

• Transpulmonary artery gradients TPG (mmHg) = PAP-PAWP(mmHg)

• Fixed PVRI of 6 units or greater and /or a TPG>15mmHg that do not respond to vasodilator therapy (nitroglycerin, milinone, dobutamine, oxygen, nitric oxide) are contraindications


Donor Criteria• Meets requirements for brain death• Consent from next of kin• ABO compatible• Weight compatible (1 to 3 times recipient )• Normal echcardiogram• Age under 40 years• Normal heart morphology at harvest

Neonatal Transplantation

Fetal Listing• A heart defect currently not considered correct

able• Normal pulmonary artery anatomy• Estimated fetal weight more than 2 Kg• Greater than 35 weeks gestation• Normal chromosome• No significant extracardiac defects

Heart TransplantationIndications

Risk Factors for Transplantation

Right Atrial Heart Transplantation

• Devised by Lower and Shumway

Bicaval Heart Transplantation

• Devised by Dreyfus & simplified by Sievers et al

Postoperative Management

• Immediate treatment Isolation room with anteroom Lines & tubes are removed by progression Usually all catecholamines are used • Immunosuppression• Rejection surveillance• Graft coronary artery diseases• Childhood diseases• Growth and development• Posttransplant lymphoproliferative disease

Sequence of Immunosuppression

• The transplant recipient recognizes proteins encoded by major histocompatibility complex of donor gene, referred to human leukocyte antigen

• The macrophages react to these foreign antigen, which are then recognized by T-cells, promoting the release of interleukin-1 from the macrophages

• T-cells are stimulated, and cellular proliferation and differentation occur with production of lymphokines ( interleukin 2) & other mediators of rejection response

• The production of cytotoxic T lymphocytes, macrophages, and lymphokines attempt to bring about destruction of donor graft

Allo-immune Reaction

• T-cell activation through three signals

Immunosuppressive Action Site

Anti-CD 154 antibody has been withdrawn from clinical trial but remains of interest. FTY720 engagement of sphingosine-1-phosphate(S-1-P) receptors triggers and internalizes and alters lymphocyte recirculation, causing lymphopenia. Antagonists of chemokine receptors are also being developed in preclinical models. MPA denotes mycophenolic acid.

Rejection Surveillance

Clinical assessment• Heart rate and activity change• Atrial & ventricular ectopy & resting tachycardia Echocardiography• LVED dimension increase of 20%• LV posterior wall thickness increase of 20%• LV shortening fraction decrease of 20% Endomyocardial biopsy• Analysis of humoral and vascular rejection• Initially every 2 weeks during 1-3 months• Monthly during 3-6 months• Repeated every 3-6 months until 2 years

Graft Coronary Artery Disease

Potential etiology• Chronic cellular rejection episodes• Hyperlipidemia• Cytomegalovirus infection• Vascular rejection Characteristics• Concentric intimal proliferation with intact internal

elastic laminae and is different from naturally occuring atherosclerosis

• The media is normal and thickened intima consists of smooth muscle cells with macrophages


Posttransplant tricuspid regurgitation• Complication of the endomyocardial biopsy procedure• The presence of pulmonary hypertension may cause rig

ht ventricular and annular dilatation, causing TR• Superimposition of pulmonary injury or right ventricul

ar dysfunction may contribute to a process leading to development of TR.

• Right ventricular dysfunction can be caused in the intraoperative period by preservation or reperfusion injury, air embolus, donor risk factors, or accelerated rejection.

• Distortion of the right atrial–right ventricular relationship caused by the implantation technique.

Heterotopic Heart Transplantation

Heterotopic transplant in Children 1 Advantages 1) Better use of donor organ 2) Suitability of procedure in high PVR 3) Survival not entirely dependent on donor organ 4) Possible recovery of the recipient heart 2 Disadvantages 1) Lack of wider experience and data 2) Technical problems related to the size 3) Doubt about the reversibility of the PVR

Heterotopic Heart Transplantation

Indications

1. Presence of fixed high PVR

2. Availability of undersized donor

3. Expectation of a certain degree of

recipient heart recovery

Transplantation Immunology• Primary immune response 1. Recognition of substance as nonself 2. Proliferation of immunocompetent cells 3. Effector phase

Antigen (HLA) Most important antigen in human coded for the genes of major histocompatibility complex and these genes are present on the 6th chromosome

• Antibody(immunoglogulin) IgG, M, A, D, E

• Complement system Composed by protein and activated by classic pathway, and alternative pathway

Immunologic Concepts

• Immunological tolerance

• Negative selection

• Autograft

• Isograft, syngeneic homograft

• Allograft, homograft

• Xenograft, heterograft

Special Immune Cells• T Cell 1. Cytotoxic T cell ; class I proteins of MHC (HLA-A,B,C)

2. Helper T cell ; class II protein of MHC (HLA-Dr)

3. T cell producing delayed hypersensitivity (T-DTH)

; class III protein of MHC (HLA-Dr)

4. Suppresser cell (Ts) ; release suppress factor

TH – OKT4, TS – OKT5

• Killer or K-lymphocyte Non B, non T cell, subpopulation of nonphagocytic monocyte.

K-cells have a receptor for the Fc portion of immunoglobulin and are the effector cells of Ab-dependant cellular cytotoxicity.

Acute Cellular RejectionISHLT categories(Grade)• G 0 ; No evidence of cellular rejection• G 1A ; Focal perivascular or interstitial infiltrate without myocyte injury • G 1B ; Multifocal or diffuse sparse infiltrate without myocyte injury• G 2 ; Single focus of dense infiltrate with myocyte injury• G 3A ; Multifocal dense infiltrates with myocyte injury• G 3B ; Diffuse, dense infiltrates with myocyte injury• G 4 ; Diffuse and extensive polymorphous infiltrate with myocyte injury; may have hemorrhage, edema, microvasvular injury

Accelerated Graft Rejection

Mechanism with elevated Troponin-T donor 1. Increased vascular permeability allowing early post-transplant infiltration 2. Activation of nonspecific inflammatory mediator 1) Lead to increased expression of donor histocompatibility antigen 2) Increase in passenger leucocyte interact aggressively with recipient lymphocyte

Class of Immunosuppressives

Use of Sirolimus Methods of cyclosporin change

Common Immunosuppressives

1. OKT3 (murine monoclonal antibody) Pan T-cell agent against the CD3 antigen on all T-cell

2. Antilymphocyte serum

3. Antithymocyte globulin

4. RATG (pan-anti T-cell globulin)

5. Monoclonal murine anti-T cell antibody

Immunosuppressive AgentsClass and Agent ActionAntiinflammatory SteroidAdrenocorticosteroids Multiple mechanisms of action. Decrease production of γ-interferon and interleukins, impair macrophage function, and decease circulating lymphocytes.Inhibitors of Interleukin-2Cyclosporin A Blocks production and release of interleukin-2, which is essential for proliferation of cytotoxic and helper T cells. Reduces interleukin-1 release from macrophages.Tacrolimus Blinds to T-cell binding protein to prevent synthesis of interleukin-2 and other lymphokins.Rapamycin Investigational agent with action similar to cyclosporine and tacrolimus.Interleukin-2 Receptor Blockers Daclizumab Humanized interleukin-2 receptor blocker prevents interleukin-2 to cytotoxic and helper T cells necessary for cell proliferation.Basiliximab(simulect) Chimeric monoclonal antibody, single IV, 12mg/BSA, on day 0, 4th for prophylaxis , not treatment

Immunosuppressive AgentsClass and Agent ActionInhibitors of Purine BiosynthesisAzathioprine Purine antimetabolite metabolized to 6-mercaptopurine, which inhibits DNA and RNA synthesisMethotrexate Folic acid analog inhibits dihydrofolate reductase, thus inhibiting purine synthesis.Cyclophosphamide A type of nitrogen mustard is activated by cytochrome P450 in liver to form an alkylating species cross-linking DNAMycorphenolate mofetil Inhibits guanosine monophosphate synthesis primarily in T and B lymphocytes, thereby inhibiting purine synthesis DNA and RNA synthesis.Immunosuppressant Gamma GlobulinOKT3 (anti-CD3 antibody) Murine monoclonal lgG antibody raised against the CD3 receptor-complex, which is present on 95% of all T cells. Antibody binding causes both removal of receptors from cells and removal of cells from the circulation.Antithymocyte globulin Polyclonal T-cell antibodies derived from injecting rabbits, goats, or horses with human lymphocytes or lymphoblasts. Antibodies formed are against a variety of human lymphocytes.

Pediatric Immnusuppression

Pediatric Heart Transplant Immunosuppression-ISHLT,2001

Percentage of Children on Various Immunosuppression Drugs

Posttransplant CSA Tacrolimus Azathioprine MMF Prednisone

Discharge 80 15 75 15 75

Year 1 75 25 65 20 70

Year 3 75 25 55 25 50

Risk Factors for Rejection Incremental Risk Factors Hazard Phase P value

for a Rejection Episode Early Constant

(Younger) Patient age at transplant - .001(Female) Gender - .002 Patient-donor interaction (Female) Gender of donor - .002(Higher) Number of HLA mismatches - .008 Procedural Globat myocardial isochemic time - .01 Immunosuppression Trip drug + induction therapy .006 Posttransplantation(Shorter) Interval since transplantation ＜ .0001(Increased) No. of previous rejection episodes <.0001

Pediatric Heart Transplantation

Pediatric heart transplantation actuarial survival (1982-1999)

Results

Pediatric Heart Transplantation

Pediatric heart transplantation actuarial survival by era

Results

Lung Transplantation

• Cystic fibrosis • Primary pulmonary hypertension• Interstitial lung disease• Congenital heart disease with Eisenmenger syn

drome• Others such as obliterative bronchiolitis, bronc

hopulmonary dysplasia, bronchiectasis

End-stage respiratory failure as a result of

Donor Selection CriteriaCriteria for living donor lobar transplantation

Age ＜ 55 years

No significant past medical history

No recent viral infections

Normal echocardiogram

Normal electrocardiogram

Normal chest radiograph

Oxygen tension ＞ 80mm Hg on room air

FEV₁and FVC ＞ 85% predicted

No significant pulmonary pathology on CT

No previous thoracic operation on donor side

Preservation of Heart & Lung

Single Left Lung Harvest

Single Left Lung Harvest

• The lung is triple bagged in a sterile plastic

container with iced saline slush for transport

Single Left Lung Transplantation

Anastomosis of donor pulmonary vein to recipient left atrium, pulmonary artery and bronchus

Bronchiolitis Obliterans SyndromeScoring system

0. No significant abnormality: FEV₁ ＞ 80% of baseline value

a. Without pathologic evidence of obliterative bronchiolitis

b. With pathologic evidence of obliterative bronchiolitis

1. Mild BOS: FEV₁66%-80% of baseline value



2. Moderate BOS: FEV₁51%-65% of baseline value



3. Severe BOS: FEV₁50% or less of baseline value



Pulmonary RejectionClassification & grading

A. Acute rejection-solitary or multiple B*. Airway inflammation-lymphocytic perivascular and interstitial bronchitis/bronchiolitis mononudear cell infitrates present Grade B0: none with/without B* Grade B1: minimal Grade 0:none Grade B2: moderate Grade 1: minimal (scattered infiltrates ) Grade B3: severe Grade 2: mild (frequent infiltrates) Grade BX: ungradeable Grade 3: moderate (dense infiltrates) Grade 4: severe (diffuse infiltrates)

C. Chronic airway rejection-bronchiolitis obliterans

Active (fibrosis with infiltrates)

Inactive (fibrous scarring without infiltrates)

D. Chronic vascular rejection-accelerated graft vascular sclerosis

Lung TransplantationImmunosuppressive protocol

INTRAOPERATIVEMethylprednisolone 15 mg/kg ⅣAzathioprine 2.5mg/kg Ⅳ

POSTOPERATIVEAtgam: day 1 = 15 mg/kg Ⅳ day 2 = 10 mg/kg Ⅵ day 3 = 7.5 mg/kg ⅣMethylprednisolone 15 mg/kg/day in 3 divided doses;Ⅳ when taking PO, then prednisone 0.5 mg/kg/day

Azathioprine 2 mg/kg and then switch to POⅣCyclosporine (Neoral) 10-20 mg/kg/day PO divided in two doses

if patient older than 6 years of age, three doses if younger than

6 years of age

Documents

Cardiomyopathy, End-stage Heart Disease & Transplantation Seoul National University Hospital Department of Thoracic & Cardiovascular Surgery