Cardiomyopathy, End-stage Heart Disease & Transplantation Seoul National University Hospital Department of Thoracic & Cardiovascular Surgery
Hypertrophic Cardiomyopathy
Hypertrophic Cardiomyopathy Definition A myocardial disease characterized by left and/or right ventricular 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.
Hypertrophic Cardiomyopathy 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").
Hypertrophic Cardiomyopathy 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 Cardiomyopathy Characteristics 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.
Hypertrophic Cardiomyopathy Etiology HCM is a genetically determined disorder of cardiac muscle 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.
Hypertrophic 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 Cardiomyopathy Morphology 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
Hypertrophic Cardiomyopathy 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
Hypertrophic Cardiomyopathy Mitral regurgitation SAM of the anterior leaflet is a constant features of classic HOCM. It is likely that severity of mitral regurgitation, magnitude 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 anuloplasty ring
Systolic Anterior Motion Proposed Mechanism
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
Hypertrophic Cardiomyopathy Postoperative care LAP of 16-18 mmHg required early postoperatively for adequate volume Digitalis, beta-receptor agonist should be avoided Hypovolemia and nitroglycerin, which can reduce LV volume and exaggerate any residual gradient, should be avoided. Atrial fibrillation may be poorly tolerated This can be best accomplished by use of beta-adrenergic receptor blocking agents ( propranolol ), calcium antagonists ( verapamil, diltiazem ), or amiodarone
Results of Operation Early death Time-related survival Mode of death 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 operative 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
Hypertrophic Cardiomyopathy Indications for operation Symptomatic patients after appropriate medical therapy, 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 common 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 Failure Natural 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 clinical myocardial dysfunction The disease process results in morphologic changes 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 one 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
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, occasionally 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 Cardiomyopathy Clinical features & diagnosis DCM frequently is of unknown etiology Speculation as to possible progression of infective, particularly 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 late, decreased left ventricular compliance may develop Al forms of cardiomyopathy may have a nonspecific prodromal phase, lasting weeks or months
Dilated Cardiomyopathy Natural 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 removal may induce hemodynamic improvement A few patients with dilated cardiomyopathy recover spontaneously. Mode of death is usually chronic cardiac failure, or occasionally intractable arrhythmias, and sometimes sudden
Dilated Cardiomyopathy Risk factors for death Marked cardiomegaly Pulmonary hypertension Elevated right atrial pressure Thromboembolism in great LV with atrial fibrillation
Restrictive Cardiomyopathy Definition A cardiac muscle disease that results in impaired diastolic 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
Endomyocardial Fibroelastosis Definition A form of restrictive cardiomyopathy with unknown etiology in which the pathologic process is restricted to the endocardium Morphology Fibrous endocardial lesions involving primarily the inflow portions of right and left ventricles The outflow of the ventricle is usually spared. Both ventricles are commonly involved, but 40% purely in 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 Fibroelastosis Clinical features & diagnosis As progressively increasing endomyocardial fibrosis develops, 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 Cardiomyopathies
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 Failure Drug 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
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 disease 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 Reduction 1. Increases in end-systolic elastance & preload recruitable 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 geometry Further diminishes volume overload by mitral valve repair when appropriate
Overlapping Ventriculoplasty
Septal Aneurysm Patch Exclusion
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 tricuspid annulus plane systolic excursion Regional asynergy without dilation of the 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 transplantation 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
Heart Transplantation 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
Heart Transplantation Donor Criteria Meets requirements for brain death Consent from next of kin 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 correctable Normal pulmonary artery anatomy Estimated fetal weight more than 2 Kg Greater than 35 weeks gestation Normal chromosome No significant extracardiac defects
Heart Transplantation
Risk Factors for Transplantation
Right Atrial Heart Transplantation
Bicaval Heart Transplantation
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
Immunosuppressive Action Site
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
Heart Transplantation Posttransplant tricuspid regurgitation Complication of the endomyocardial biopsy procedure The presence of pulmonary hypertension may cause right ventricular and annular dilatation, causing TR Superimposition of pulmonary injury or right ventricular 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 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 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 Rejection ISHLT 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
Common Immunosuppressives OKT3 (murine monoclonal antibody) Pan T-cell agent against the CD3 antigen on all T-cell Antilymphocyte serum Antithymocyte globulin RATG (pan-anti T-cell globulin) Monoclonal murine anti-T cell antibody
Immunosuppressive Agents
Immunosuppressive Agents
Pediatric Immnusuppression
Risk Factors for Rejection
Pediatric Heart Transplantation
Pediatric Heart Transplantation Pediatric heart transplantation actuarial survival by era
Lung Transplantation Cystic fibrosis Primary pulmonary hypertension Interstitial lung disease Congenital heart disease with Eisenmenger syndrome Others such as obliterative bronchiolitis, bronchopulmonary dysplasia, bronchiectasis
Donor Selection Criteria
Preservation of Heart & Lung
Single Left Lung Harvest
Single Left Lung Harvest
Single Left Lung Transplantation
Bronchiolitis Obliterans Syndrome
Pulmonary Rejection
Lung Transplantation
Do'stlaringiz bilan baham: |