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Heart valve transplantation is referred to as the golden as the incidence of heart valve disease is on the rise. It is estimated that the number of heart valve replacements will triple over the next few decades. There is also a higher risk of death in sensitized patients undergoing heart valve transplant due to antibody mediated rejection. Heart valves transplant can be either allograft or xenografts. A number of factors are accountable for allograft failure. This paper talks about the types of heart diseases including stenosis and valve regurgitation and the source of heart valves being either biological or tissue engineered. Risk of heart valve failure is minimized by administration of immunosuppressants as they aid in delaying an immune response. Any rejection is manifested in the increased expression of cytokines like IL-2, IL-4, and IFN-ϒ. A number of novel techniques have emerged in the replacement and repair of heart valves increasing the life span of individuals.
The review paper includes the following contents:
Cardiovascular diseases are no longer said to affect people as they age; it is a disease that affects people in the prime years of their lives with deaths occurring both in men and in women. The incidence of heart failure is on the rise and the aortic valve transplantation is said to the golden therapy in today's world to an individual suffering from severe stenosis. The number of patients being on the rise and the eligible donors in lesser numbers. (1). The first attempt of reconstruction of a mitral valve was made by Soutter in 1925.The introduction of as cardiopulmonary bypass by Gibbson which gave rise to mitral heart repair in 1953.(2) .
Studies have proved that the incidence of heart valve disease is said to have increased with age and growth. Statistics have showed that one in eight people above the age of 75 yrs are said to suffer from valve disease. The root cause of this disease involves calcification of the leaflets, degenerations or congenital malformations, rheumatic fever, endocarditis and so on which mainly affects the left side valves of the heart(3). Statistics have shown that the ten-year survival in individuals suffering from congenital heart disease (CHD) is now exceeding over 90% and in the relatively rare cardiomyopathy(CMP) is around 68%.(4)
The major requirement of heart valves is that they show high flexibility, durability and tensile strength and the leaflets open and close at regulated intervals. Utmost care should be taken that they don't lead to thrombosis. The use of tissue engineered scaffolds either with or without the presence of freshly derived autologous cells may represent the tissue engineering heart valve paradigm of the year.(3)
Selection of a particular heart valve prostheses depend upon a patients characteristics like tolerance, life expectancy and the use of certain anticoagulants associated post the operation (3). The term tissue engineering coined by Langer and Vacanti was said to encompass isolation of cells from a source, seeding of the cells onto a scaffold, tissue formation followed by implantation into the system. Here it exploits the body's capability of tissue regeneration (3).
Immunosuppressive drugs are said to play a crucial role in different type of transplantation as it helps prevent allograft rejection. But these drugs are also said to have a number of limitations which leads to decrease in their application.(5)
TYPES OF HEART VALVES
During heart valve replacements there are two types of valves including mechanical and bioprostheses valves. Both types of valves are said to have their set of advantages and disadvantages. The mechanical valves are said to have a long lasting structural durability whereas the bioprostheses are said to undergo structural degeneration and progressive calcification. Choice of mechanical valves comes with a lifetime of anticoagulant therapy which reduces the risk of hemorrhage and thromboembolism but avoids the burden of operation required in bioprostheses.(3) Mechanical valves are said to last a life time and the anticoagulation treatment given with Warfarin will reduce the formation of any types of blood clots but conversely on the other hand use of prosthetic valves taken from either humans or animals avoids the use of any anticoagulants but has a shorter life span.(3)
Biologically derived heart valves are said to show a lower incidence of thromoembolism and endocarditis and have a higher growth rate but it also has its limitations including higher rate of calcification, deterioration and are prone to greater immunologic response whereas in the case of tissue engineered heart valves there is more durability and it is more biocompatible.(6) the scaffold for the mechanical heart was made of polyurethane and is said to form a sheet over which the endothelial cells are overlaid and get attaches to the scaffold by adhesion molecules or certain extracellular matrix proteins .(6) polyurethane is a synthetic non immunogenic and non thrombotic synthetic material.
BIOLOGICAL HEART VALVES
Biological heart valves taken from animal tissue like from pigs, cows or horses are called xenografts whereas those taken from humans by donation of his or her heart are called a allograft or a homograft. (7)
TISSUE ENGINEERED HEART VALVES
Seeding of the cells is done either by dynamic cultivation or by static cultivation. Application of shear stress during dynamic cultivation causes the induction of pro inflammatory cytokines who are said to be an inducer of monocyte endothelial interactions. Seeding of the scaffold with fibroblast as well as endothelial cells reduces the incidence of an inflammatory response as compared to the use of endothelial cells alone ().IL-1 and VCAM are expressed at lower level whereas expression of IL-8 increase. This further increases the risk of arteriosclerosis and coagulation as a result of monocyte activation. The signs of stress few days after the surgery are observed by increase in the amount of IL-6, IL-8 and MCP- 1(8)
A new addition in the field of tissue engineered heart valve is the use of a certain polyelectrolyte multilayer film called Heparin- vascular endothelial growth factor (VEGF) multilayer film which said to not only be an antithrombotic coating as heparin is said to be an anticoagulant but also is a stimulator to progenitor endothelial cells. This layer is said to decrease the incidence of platelet adhesion and thus improve haemocompatibilty. Thus it is called antiplatelet coating reagent on decellularised valves. VEGF is said to aid in the attachment and proliferation of endothelial progenitor cells. (9)
A procedure called Ross method carried out by replacing the infected aortic valve by a pulmonary valve was said to be a failure because of certain biochemical demands.
CAUSES OF HEART VALVE DISEASES
Some of the main reasons that lead to an injury or damage to the heart valve maybe due to heart attack, rheumatic fever, any wear and tear in the he heart or even due to any infection.(7) the main valves affected are the mitral ,aortic valves, the pulmonary valves and the tricuspid valves as they are subjected to high pressure. Based on this heart valve diseases are divided into two types a) stenosis and b) valve regurgitation/incompetence(3). In stenosis the flaps present in the valves of the heart which open and close get damaged. This further leads to the narrowing, stiffness or thickening of the valves which restricts the flow of blood through it. Thus the valve becomes rigid and causes the heart to work much harder and thus leads to further thickening (3). In valve regurgitation the heart valve does not close properly and hence there is leakage and a high possibility the blood will flow backwards. This puts pressure on the heart and hence it dialates and causes stretching and thickening of the heart.(3)
The causes of heart disease can be either congenital i.e. from birth or it can be acquired during one's life. Congenital heart diseases usually affect the pulmonary and the aortic valves due to improper size. Acquired heart valve disease usually occurs due to a particular infection which affects the heart valves like rheumatic fever or endocarditis. Other causes maybe due to heart attack , heart aneurysm or coronary heart disease. (10)
Further it was observed that there were abnormalities associated with the mitral valve including type I, normal leaflet motion; type I I, prolapsed leaflet; and type III, restricted leaflet motion. The clinical manifestations in type 1 is swelling in the leaflets , type 2 is the prolapsed of one of the leaflets more than the other and type 3 thickening of the leaflet.(10)
Pulmonary valve endocartitis is another heart valve illness seen mainly in patients with high drug consumption or undergoing hemodialysis or any congenital heart disease(11) Studies show that the main causative agents of heart valve endocartitis is Streptococcus viridans and Staphylococcus aureus . A patient with severe mitral stenosis and cardiac lesions is also a factor which leads to the formation of endocardtitis.(12)
Clinical manifestations of pulmonary valve endocartitis are fever and rise of serum markers of inflammation differentiate septic pulmonary embolism. Other symptoms of infective endocartitis involve fever, chills, anorexia, and dyspnea. Severe cases which lead to surgery are indicated with persistant fever. (11)
PRECAUTION BRFORE A HEART VALVE SURGERY
Before any transplantation is carried out various tests are performed to prevent organ rejection. One of the techniques involves ABO blood group compatibility tests to prevent hyper acute rejection. Also it is observed that Minor ABO mismatches do not adversely affect 1-year outcomes of heart transplantation and hence will help to facilitate organ allocation for end-stage heart failure patients, thereby reducing waiting time for heart transplantation.(13)
HEART VALVE SURGERY
Heart valve transplantation involves heart valve engineering utilizing scaffolds materials which maybe either a xenograft or a homograft and is said to have the same geometry and physiological features as the native part which is said to be fixed with gluteraldehyde to mask or block the immunogenic epitopes and thus making it unsuitable for use. Solution to this is the removal of cells or decellularisation either by the use of trypsin or EDTA or by using less harsher conditions like detergents namely sodium deoxycholate or SDS which does not affect the matrix integrity. But inspite of this there are still traces of original cells which is said to help in tissue regeneration. With the several advantages of these scaffolds there are some limitations to their use . In the case of xenografts there is a possibility of formation of zoonoses and in the case of honografts there is a small number of donor grafts (3).
In heart valve remodeling the material used has to be biodegradable and biocompatible. The most commonly used materials for synthetic valves were polyglycolic acid (PGA), polylactic acid, poly 4 hydroxybutyrate and polcaprolactone.(3)
The tissue obtained for xenograft or allograft from different sources is said to be stored at 4 ËšC and fixed by gluteraldehyde which will help reduce the antigenic determinants and kill he living cells (14).
Retention of any antigenic determinants would result in calcified valves due to thickening and shrinkage and hence fixing with gluteraldehyde is important.(14)
Studies have also shown that treatment of allografts with gluteraldehyde are said to result in heart failure after 12 weeks due to calcification of the heart valves whereas treatment of the allograft with antibiotic cold solution resulted in mitral regurgitation after 19 weeks.(15)
FACTORS INFLUENCING LATE ALLOGRAFT VALVE FAILURE
Studies conducted have shown that the quality of the donors valve plays an impotant role in transplantation. Any form of structural impairement like lacerations , lesions artheroma ,calcific depositions lead to allograft valve failure. Age is said to play an important role wherein proven results of allograft above the age of 55 yrs are said to be incompetent because age related changes in the valve connective tissue leads to destruction with age.(16)
Contradictory to this it was observed that allograft below the donor age of 33 yrs for right ventricular outflow reconstruction posed a greater risk factor. Ultimately they came to a conclusion that there is a greater relevance between the donors and recipients age to the survival of the valve graft rather than their ages taken separately. Hence the optimum donors age was between 50-55 yrs of age.(16)
2) HOST FACTORS
Many cases have shown that there is a high frequency of allograft failure at a younger recipient's age. This implies that the durability of the valve allograft decreases at a younger age. Hence statistics show that viability was maximum for those older than 10 years (81%) ,61% for patients between and 25% for patients less than a year old. Reasons for this may be either due to immunologic response of the body, outgrowth of the implanted allograft wherein there is an increase in the size of the heart and the pulmonary artery leading to annular dilation, stenosis and increased hemodynamic demands. Another factor leading to failure is allograft size leading to hemodynamic impact which causes incompetence.(16)
3) METHOD OF INSERTION
From the four methods of implantation involving subcoronary 120-deg rotation, subcoronary intact noncoronary sinus, aortic root replacement or aortic root inclusion (mini root or cylinder) the root replacements are considered to be of greatest advantage with no valve failure. (16)
4) VALVE PROCUREMENT, PROCESSING AND STORAGE FACTORS
Cryopreserved valves or antibiotic preserved valves are some of the methods of storing allografts prior to transplantation. The cryopreserved grafts were said to be less antigenic because of the loss of any antigenic determinants. Studies also showed that longer ischaemic times reduced the allograft viability. Thus the ischaemic time is determined by the required t prevent the expression of any antigens like the HLA and the time conducive to inducing the expression of connective matrix and fibroblast cell viability.(16) The storage of heart valve allografts at 4 C cell viability is said to show attenuation in the immunogenicity and the antigenicity of the cells. After a period of 21 days the endothelial cell viability is said to decrease.(17) The use of cryopreserved grafts are said to show a high degree of viable endothelial cells which express surface antigens. Mostly in these cases there is chronic tissue change which can further cause destruction of the allograft. (18)
IMMUNOLOGIC RESPONSE AFTER HEART VALVE TRANSPLANTATION
It is important to note the immunologic response of the recipient post any transplantation procedure. As we know that T-Helper cell play a major role in humoral and cell mediated immune response and thus indication of an increase in the number of circulating donor-specific helper T lymphocytes precursors (HTLp) signifies any tissue rejection in the body. Hence during transplantation the presence of B and T cells as well as macrophages is a symbol of any rejection. The manifestation of donor specific immune response along with the antibodies against HLA class 1 and 2 is observed. (19).
An immunologic repose after transplantation manifests itself by the increase in the number of helper T-cells precursors and severe damage to myocytes and infiltration occurs in valve allograft transplantation where there is excess production of IL-2 which is said to evade al the immunosuppressant and produces a cellular and a humoral response. The presence of these donor specific T-cells can modulate the presence of other immune competent which will reject the transplant(18). this is an important parameter in tissue rejection(20). The incidences of these cells were seen in large amounts in spleen and peripheral blood. Also donor specific cytotoxic T lymphocytes precursors and their high avidity fraction play an important role in tissue rejection. (21)
One way of detection of acute rejection is by studying the pattern of mRNA expression of different cytokines. Studies have shown that allograft reaction induce the expression of a number of cytokines including IL-1a, IL-2, IL-4, IL-6 ,IFN-ϒ conversely the presence of IL-10 and IL-4 play a role in suppression of rejection and immunological reactions. The study of the cytokine genes by RT-PCR is studied (22) .The presence of T-cells was determined by expression of the cytokine gene was studied by analyzing the constant region of the β chain in the TCR receptor (22). Also it is observed that the cytokines IL-6 and IL-10 are not released only by T-cells but also by monocytes and endothelial cells. Surprisingly it is seen that IL-10 is present both before and after transplantation. (22)
Blood group antigens (ABO) and Human Leucocyte Antigens (HIA) are regarded as antigens which are able to provoke a strong immune response in antigen incompatible organ or tissue transplantation. It was also observed that the use of fresh tissue for allograft transplantation activates class 1 and 2 homonuclear blood cells whereas use of cryopreserved tissue causes decrease in the activity. The increase in the number of activated lymphocytes is seen immediately after the transplantation in donor recipient mismatch. accumulation of IL-2 producing T cells in the graft plays an important role in rejection.(23) the proper functioning was monitored using transoesophageal, transthoracic, and/or epicardial echocardiography. Anti coagulants were added such as wafarin and aspirin.(24)
Very late response to transplantation is seen with regards to complement cascade activation involving the presence of the complement components C3d and C4d mainly due to an antibody mediated rejection process. (25)
Biomechanical remodelling is a process in which different tissues in order to adapt to their surroundings undergo differentiation and they change their shape to fit into their environment. There are two factor that regulate tissue biomechanics in post natal valves namely serotonin and transforming growth factor (TGFβ). These factors in synergism with one another are said to increase biomechanical stiffness. Thus TGFβ is considered a effective stimulator in valve stiffening association with serotonin.(6)
Since the past times the in order to increase the durability of the grafts by removal of the cells that cause stimulation of an immune response but this method is said to damage the matrix proteins and decrease the mechanical strength . A novel technique called anticalcinosis devitalisation of the allograft is done using digitonin and calcium binding with EDTA causing faster death of the donor cells and reduces incidence of calcinosis. Digitonin is a detergent which damages the cell and EDTA is said to prevent the accumulation of calcium by chelation and thus prevent calcinosis. Signs of immune response was observed by leukocyte infiltration.(26)
POSTOPERATIVE CLINICAL CONDITIONS
Administration of immunosuppressants
Immunosuppressive treatment called cytolytic induction therapy wherein ATG (anti thymocyte globulin) treatment is given to patient. Sometimes this treatment is followed by t cell adapted therapy. Furthermore additional immune suppressive therapy is administered by the use of methyl prednisolone, azathioprine and cyclosporine A called the triple therapy.
This was performed after every first third, fifth , seventh month after heart valve transplant using an ultrasound. The valve assessment was done using colour Doppler four-chamber view. The left ventricular cystolic rates are measured.
Right heart catheterization is performed which mainly helps study the pressure load across the valves seen mainly in aortic sclerosis.(13)
One of the complications involved in heart transplant is tricuspid regurgitation (TR). This mainly causes certain tricuspid damage. In tricuspid valve transplantation the use of a biotome to take a biopsy sample is said to cause damage to the tricuspid valve.(13)
Following removal of transplanted heart from bypass the heart is said to be under pressure of the recipient which causes heart failure. This chronic ventricular pressure causes tricuspid insufficiency.(13)
The standard therapy of transplantation has lead to increased pulmonary hypertension , increased oxygen uptake and tricuspid regurgitation.(13)
LIMITATIONS OF HEART VALVE TRANSPLANT
Studies have shown that thromoembolism incidence is lesser in the mitral valve repair s compared to mitral valve replacement. Sometimes the failure of the replaced valve occurs because of degenerative diseases. But the rates of any reoperation are said to be much lower when compared to prosthetic valves.(27)
Studies showed that complications associated with LVAD (left ventricular assist device (LVAD) has lead to the formation of right ventricular dysfunction which manifests itself as a disturbed interaction or connection between the left and the right ventricle which causes a deformation or change in the shape of the right ventricle and causes the septum to shift from the left to the right and hence reduces the availability of the septum to the right contractility. (28)
One way of reducing the risk of right, ventricular dysfunction is in the application of echocardiography, which helps monitor the septal deviation. Also in order to improve the clinical condition of patients with LVAD the proper functioning of the tricuspid valve plays an important role.(28)
Questions were raised whether a use of a stentless valve is as effective as the use of a homograft. It was observed that the rate of reinfection rate after the use of homograft was said to be 3.8%-6.8% whereas in the case of stentless valve the rate of reinfection was found to be 8.6%. dependingf in the severity of the diusease the stentless prostheses valve can be either implanted in the subcoronory position or the total root replacement(5).
Many cases have showed that there is high incidence of heart valve allografts in infants as compared to middle-aged group individuals probably due to an immune response elicitated by the pediatric group. Uptill date there is no drug that can stop or delay the immune response and hence help in prolonged survival of the allograft. But discovery of a variety of drugs called immunosuppressants such as cyclosporine A, FK 506 and rapamycin which delay the T-cell activation. Transplantation of valved allografts into the infrarenal aorta involved removal of little myocardium from the allografts followed by ligation of the coronary arterial segments.(29) The treatment with cyclosporine should be over a period of 14-28 days and a duration of 7 days is too short .(16)
Sometimes it is observed that there are many limitations associated with the use of immunosuppressive drugs like failure to support tolerance induction, lack of antigenic specificity and even morbidity. The use of tolerogenic dendritic cells is new method used to reduce the application of immunosuppressive drugs. These cells are said to have low levels of MHC molecules, low level of co-simulation and impairment in production of cytokines. These cells are used to develop negative cellular vaccines. (5)
Another complication after cardiovascular surgery is atrial fibrillation. A number of factors predisposing to it include increase in the pressure, impaired ventricular function , inflammation, fever and anemia. Landiolol hydrochloride is a β andrenergic blocker which said to prevent this atrial fibrillation from occurring and has a comparative lower potency then esmolol. (30)
To ebb the complications and limitations of using valvular prostheses certain substitutes for heart valve are found which are said to have a high regeneration and growth potential.
There are two approaches by which stem cells can be used for heart valve transplantation. These include the in vivo and ex vivo approaches. The in vivo approach involves isolation of the cells, seeding onto the scaffold and implantation into the patient and allow growth of cells whereas the ex vivo involves the direct implantation of synthetic of naturally derived valve seeded with cells implanted into the patient.
Bone marrow derived mononuclear cells are said to be used in preparation of tissue engineered valvular grafts. Living vascular grafts were prepared using biodegradable tubes which are said to be seeded with autologous cells and these BMC seeded cells are said to aid in heart valve transplantation.(24)
The first step in this procedure involves making of the scaffold non-woven polyglycolic acid meshes and coated with poly hydroxybutyrate and fixed with stents. The next step involves isolation of the bone marrow derived mononuclear cells and the viability of cells was checked by flow cytometry and tryphan blue staining. Following this the cells were fixed with methanol and treated with immunofluorescence using different epitopes namely CD45, CD34, CD146, CD90, CD166, CD44,
Hence the cells are layered into the scaffolds using fibrin. Mesenchymal stem cells obtained from bone marrow were said to differentiate into osteocytic and adipositic cells. After the heart valve transplantation the functionality and the position of the graft is checked by angiography (31). Staining showed the presence of factors like CD44, CD45 and CD15. Flow cytometry showed the presence of lymphocytes and momocytes. Hemotopoietic stem cells as well as MCs with CD44 are present. (24)
Stem cells are said to increase the versatility of heart valve transplant by using heart valve tissue engineering and to reduce the limitations shown by vascular derived cell. Possible sources include cells isolated from blood, bone marrow, adipose tissue, amniotic fluid, chorionic villi, umbilical cord and induced pluripotent stem cells.(31)
Stem cells are obtained from different sources namely the bone marrow derived mesodermal cells which is used as a fabrication in heart valves and is said to form a stromal layer of cells. Secondly the bone marrow derived mononuclear cells in heart valve repair mainly done in infants with a congenital heart disease. The next source is adipose derived mesenchymal stem cells which have characteristics of epithelial progenitor cells. Also another source used is the amniotic fluid derived endothelial progenitor cells. The use of endothelial cells is of a greater advantage as it reduces the risks of coagulation and any inflammatory response.(31)
It has been observed that bone marrow cells can differentiate, proliferate and grow at high rate. Inflammated mediated process is seen in the BMC seeded grafts which give rise functional blood vessels.(31)
In the case of infants source of cells for heart valve transplant is limited. The human placenta is said to be a good source for mesenchymal progenitor cells. In this technique it involves the use of novel cells likeusing human prenatal progenitor cells derived from chorionic villi and umbilical cord blood which is a good source of fabrication in heart valve transplantation.(32) The umbilical cord derived cells mature into endothelial cells and form layers in the heart valve scaffold and forms a non thrombogenic cell layer with a high growth potential.
Another innovation in the heart valve transplantation is the use of ECG-gated and triggered multi detector computed tomography (MDCT) technology which helps in the visualization of the prosthetic heart valve and also the detection of endocarditis.(33)
A method called left ventricular remodeling is carried out after myocardial infarction wherein a well regulated inflammatory response and a scar which will prevent the expansion of the infarction. The regulation of inflammatory response plays a major in myocardial infarction. Studies showed that a dose of dexamethasone showed favorable results in the mouse model and complete repression of inflammation was said to have a negative outcome. (33)
A technique wherein there is minimal use of surgical techniques wherein right parasternal incisiona is made and the pericardium is opened. The abnormalities of any subvalvular portions are reconstructed using polytetrafluoroethylene suture material. Similarly in the case of endocarditis treatment is done either by polytetrafloroethylene replacement or by using a pericardial patch mechanism.
One of the methods required for monitoring of the mitral valve is by transesophageal echocardiography (TEE) which gives us details about the severity of the infection, the site, the size of the leaflets. Reduction in the size of the leaflets is achieved by a technique called annuplasty is frequently. Another method called the Kay suture placation is also used (10).
Heart diseases are coined to be the number one killers in developed countries. They are called the leading killer and disabler. Heart valve diseases are said to be of two types namely stenosis and valve regurgitation. The reasons for this maybe due to increased pressure on the valves, certain infection and severe stenosis leads to manifestation of endocarditis. In order to resolves these problems heart valve transplantation and repairs are carried out. This procedure involves obtaining a heart valve either from biological source or a tissue engineered heart. There are in number of factors which lead to the failure in allograft transplantation. The different patterns of expression of the different cytokines which act as predisposing factors in tissue rejection. Chronic tissue rejection is observed by monitoring the mRNA expression of genes coding for different cytokines. Treatment of the patient with immunosuppressive drugs like cyclosporine both before and after transplantation helps to reduce the immune response by delaying the activation of T-cells. Different novel techniques have been introduced in making transplantation a more efficient process. Use of stem cells has proved to be a major asset in transplantation with regards to construction of heart valves.