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HEART VALVES

I. INTRODUCTION

 

1.1. Heart and Heart Valves

It is easily understood that the muscle that we call the heart must continue to pump with adequate force to pump the blood that the body needs. "Valves" however are extremely important to the heart's efficiency. These delicate structures allow for the efficient flow of blood progressively forward through the heart's chambers, maximizing the efficiency of the heart muscle's work.

In order to understand the importance of the heart valves there is a summary of the heart given below (see

Fig. 1, from www.heartpoint.com)

Ø      The Right Atrium receives "used blood" from the body. Blood will be pushed through the tricuspid

valve to the

Ø      Right Ventricle, the chamber which will pump to the lungs through the “pulmonic valve” to the

Ø      Pulmonary Arteries provide blood to both lungs. Blood is circulated through the lungs where carbon

dioxide is removed and oxygen added. It returns through the

Ø      Pulmonary Veins, which empty into the

Ø      Left Atrium, a chamber that will push the “Mitral Valve” open. Blood then passes into the

Ø      Left Ventricle. Although it doesn't always look like it in drawings done from this angle, this is the

largest and most important chamber in the heart. It pumps to the rest of the body. As it pumps, the pressure

will close the “mitral valve” and open the “aortic valve”, with blood passing through to the

Ø      Aorta, where it will be delivered to the rest of the body.

Fig. 1. The whole heart. (www.heartpoin.com)

 

1.2. Causes of Disease on Heart Valves

Congenital heart disease: Problems with the heart valves may be present from birth. For instance, so-called

"bicuspid aortic valve", being of made of two leaflets instead of three, is often associated with an accelerated

incidence of aortic stenosis that may occur when the patient is in his or her fifties. 

Rheumatic heart disease: So called "rheumatic fever”, inflammatory reaction due to some infections with

the bacteria called "streptococcus" is an example. Due to the discovery and use of antibiotics, rheumatic

fever is far less common than in the past, particularly in developed countries. Proper treatment of strep

infections can prevent almost all of the cases of rheumatic heart disease.

Fig. 2 from www.heartpoint.com

Heart attack: Specific parts of the heart muscle concerned with proper functioning of the valves can be

injured in the course of a heart attack. If there is a tear of part or all of one of the "papillary muscles", severe

mitral regurgitation can occur rapidly and require emergency therapy, perhaps including surgery.

Weakening of the supporting structures of the heart: A tear or rupture in mitral valve, which attach the

valve to its papillary muscle, can cause substantial leakage through the mitral valve. This may begin and

progress slowly, or be quite severe at the onset and require emergency surgery. Weakening of the walls of the

aorta can occur, which leads to gradual dilation of the aorta, which can then lead to substantial leakage

through the aortic valve.

Weakening of the heart muscle: Heart muscle will tend to lengthen when it weakens. As the chamber

enlarges, so too do the holes which the Mitral and Tricuspid valves are designed to cover. At some point,

while the valve itself is not diseased, it simply cannot cover this area, and “valvular regurgitation” will begin

to occur. This often leads to yet further dilation and enlargement of the ventricles, and a "vicious cycle"

begins to occur. 

Infections: Infection of a heart valve is termed "Endocarditis" is the term used for infection of a heart valve.

This is not a common problem, but it can cause rapid progression of valvular disease, generally regurgitation,

over a matter of days to weeks. This infection requires prompt diagnosis and treatment, but may still land up

requiring valve surgery even when caught early.

There are also specific heart valve problems and other less common causes of valve disease. Most common

problems are summarized below. 

Ø      Problems with the Aortic Valve: Aortic Stenosis and Aortic Regurgitation

Ø      Problems with the Mitral Valve: Mitral Stenosis and Mitral Regurgitation

Ø      Problems with the Pulmonic and Tricuspid Valves

Fig. 3. Heart, an overview showing problems. (www.heartpoint. com)

Backward flow of blood is called "regurgitation" or "insufficiency", and it is termed "Mitral Regurgitation"

or "Mitral Insufficiency" if it occurs through the Mitral Valve. Difficulty in opening the valve is called

"stenosis", and if it involves the Aortic Valve, is called "Aortic Stenosis". (See Fig. 3)

1.3. Surgery available for problems with the Valve

There are several options, depending on the exact type of problem, patient, and severity of the process as

summarized in web-site of “heartpoint.com”. For instance, in many cases of mitral regurgitation, a skilled

surgeon can repair the problems that cause leakage without the need for replacement.

Often, a valve "ring" is placed in the orifice that the mitral valve covers to "tighten up" the size of this area

and allow the valve to cover it more effectively. The size and shape of the leaflets can be carefully

remodeled, and torn structures sewn back together.  .

 

Some mitral and aortic valves simply need to be replaced. This may not be known until the actual time of

surgery, when a repair for regurgitation or a commisurotomy for stenosis can then be seen to be impossible

or ill-advised. The valvular structure is cut out, and as much of the supporting structure left as feasible. The

new valve may be mechanical or bioprosthetic (Figure 1), and may be done from a standard approach

across the breastbone ("median sternotomy"), or with some of the new "mini" approaches.

 The patient's own pulmonic valve may be replaced into the aortic or mitral position, termed as the Ross

procedure.

1.4. Artificial Valves

The two main types of valves are "Mechanical" and "Bioprosthetic". Mechanical valves have simply been

devised from scratch, and are made of metal or similar materials. Bioprosthetic valves are fashioned from

animal or human tissues. (See Fig. 4)

Fig. 4.  Artificial valves. (www.heartpoin.com)

 

Mechanical valves: There are several different varieties, including "bileaflet tilting valves" which are

extremely popular and reliable. Tilting single disc devices are also quite popular. Older models included the

"caged-ball" device and "floating discs". The body does not recognize these as "foreign", and thus there is

not a fear of rejection. Mechanical valves are generally felt to have the advantage of lasting the longest time.

Their main disadvantage compared to other types of valves is the need to take potent blood thinners, which

decreases the tendency to form clots on their surface.

Bioprosthetic valves: These use some biologic material in their composition. They are all treated, and do not

carry the risk of rejection. Treated aortic valves from human cadavers, treated pig aortic valves, and valves

fashioned from the pericardium (the outside lining of the heart) of cows are all utilized. These types of valves

do not necessarily require that the patient take blood-thinners, but generally do not last as long.

1.5. Problems in Artificial Valves

The need and ability to maintain long-term anticoagulation (blood thinning) is a very important factor.

Several classes of people may not be good candidates to take warfarin (brand name coumadin), and therefore

should receive a bioprosthetic valve. This group includes young women who wish to become pregnant. 

People who have had previous and sometimes-repeated problems with bleeding (for example, frequent

bleeding from ulcers) are often felt to be better served with the bioprosthetic valves, which do not require

anticoagulation.

On the other hand, for people who are going to need to have anticoagulation anyhow because they have the

abnormal rhythm known as atrial fibrillation, using a bioprosthetic valve would have little advantage since

they are going to need to take the blood thinner anyhow. They will most often receive a mechanical valve to

take advantage of its longer life.

As a result, valve replacements using either bioprosthetic or mechanical valves have the disadvantages that

are summarized by Toshiharu et al (1995).

Ø      They are unable to grow, repair or remodel

Ø      They are both thrombogenic and susceptible to infection

Ø      They have limited durability and longevity

II. REPORT

2.1 Alternative Solutions of Valvular Replacements

Investigations have been focused on the techniques of tissue engineering to create a living valve substitute

due to the disadvantages of valvular replacement (Fuchs et al 2001). The ideal substitute would yield

complete closure and non-obstructiveness, non-thrombogenicy, resistance to infection, inertness to

chemicals. Moreover it would be nonhemolytic, durable and easily and permanently inserted.

Over the last 6 years two basic approaches have been pursued, i.e. decellularization of xenogenic valves and

addition of cells or allowing ingrowth of host cells to occur. Bader et al (1998) suggested that tissue-

engineered valve made of autogolous cells and biocompatible scaffold having potential to remodel, repair,

and grow would be favourable option. They removed cells porcine aortic valves by detergent cell extraction

using Triton. They showed removal of the original cells while grossly maintaining the matrix. Endothelial

cells were then isolated from human saphenaus vein expanded in vitro, and seeded onto acellular matrix.

O'Brein et al (1999) suggested a different decellularization process. A composite heart valve biprosthesis was

prepared by the "SynerGraft" process after decellularization. Then the valve composites weer implanted as

pulmonary valve replacements in sheep. They reported that all valves weer hemodynamically functional at

explant.

The second approach involves traditional tissue engineering. In this approach autologous cells are

transplanted onto a biodegradable scaffold in the shape of a heart valve (For instance, Sodian et al 2000,

Teebken et al 2002, Hoerstrup et al 2002.). The tissue-engineered valve would have a potential to grow,

remodel and avoid infectious and thrombogenic complications.

2.2. Tissue Engineering

Tissue engineering has been rapidly expanding approach in order to solve the organ shortage problem. It is

an "interdisciplinary field that applies the principles and methods of engineering and the life sciences toward

the development of biological substitutes that can restore, maintain, or improve tissue function." (Fuchs et al

2001). Much progress has been made in the tissue engineering of structures relevant to cardiothoracic

surgery, including heart valves, blood vessels, myocardium, esophagus, and trachea.

Over the last 50 years, transplantation of a wide variety of tissues, reconstructive surgical techniques, and

replacement with mechanical devices have significantly improved patient outcomes (Fuchs et al 2001). The

first successful organ transplant was performed by Murray et al in 1954. Since that historic accomplishment,

the field of transplantation has evolved to include kidney, liver, split liver, pancreas, heart, lung, and small

intestine at hundreds of transplant centers throughout the United States. In 1967, Barnard performed the first

heart transplant for congestive heart failure. These strides have been made possible because of the advances

in transplantation biology and immunology leading to the development of a variety of immunosuppressive

agents

Unfortunately, organ and tissue transplantation are imperfect solutions because they are limited by a number

of factors. Worsening donor shortages result in a discrepancy between the number of patients needing

transplants and available organs.  Additionally, transplantation recipients must follow lifelong

immunosuppression regimens with their increased risks of infection, tumor development, and unwanted side

effects. Surgical reconstruction also suffers from a lack of available donor tissue and donor site morbidity.

Replacement with mechanical devices or artificial organs is limited by an increased risk of infection and

thromboembolism and finite durability. Because of the above shortcomings, the field of tissue engineering

and selective cell transplantation was born as a means to replace diseased tissue with living tissue that is

"designed and constructed to meet the needs of each individual patient" (Fuchs et al 2001).

Tissue engineering is defined as "an interdisciplinary field that applies the principles and methods of

engineering and the life sciences toward the development of biological substitutes that restore, maintain, or

improve tissue function" (Fuchs et al 2001). 

In 1975, Chick et al were the first to place pancreatic islet cells in semipermeable membranes to improve

glucose control in diabetes. Others created skin substitutes consisting of fibroblast cells seeded onto collagen

scaffolds, which are currently used in clinical practice in the context of burns and diabetic ulcers (Fuchs et al

2001). 

Today, tissue engineering efforts are being undertaken for every type of tissue and organ (See Fig. 5).

Fig. 5. Tissue engineering process (Fuchs et al 2001).

2.3. Tissue Engineered Heart Valves

Teebken et al (2002) argued that for substitution of diseased valves although human valve allografts have

become more widely used as compared to bioprosthetic and prosthetic valves they are not available due to

donor scarcity.  The use of glutaraldehyde-fixed xenografts, which are abundant, may overcome this problem

but xenografts are not viable structures.

Teebken et al (2002) analysed the processing of allogeneic and xenogeneic acellular matrix scaffolds of pulmonary heart valves after in vitro seeding with the use of autogolous cells. They found that both the decellularization process and the in vitro tissue engineering approach using acellular matrix conduit lead to in vivo reconstitution of viable heart valve tissue. However, half of the seeded tissue-engineered conduits degenerated after 9 months. They related this founding to the immonologic modulation of autologous cells during to culture period prior to implantation. As a result they concluded that new methods are to be necessary to control cell differentiation during cell expansion prior to implantation 

Christopher et al (1996) worked on tissue engineered leaflets that are constructed by serially seeding

autologous ovine fibroblast endothelial cells onto a biodegradable synthetic matrix composed of copolymer

of polyglycolic and polylactic acid. They reported that the structure and function of the tissue engineered

constructs approaches those of native tissue when they are exposed to physiological forces over an extended

period of time.

Sodian et al (2000) created a tissue-engineered trileaflet valve from porous PHA and vascular cells and

constructed it into the pulmonary position. The valves showed no thrombus formation and minimal

regurgitation. Collagen content increased over time showing continued remodelling.

Another study was performed using composite scaffolds of PGA-P4HB by Hoerstrupt et al (2000).  The

composite scaffolds were grown for 14 days in a pulse duplicator in vitro system under gradually increasing

flow and pressure. Fig. 6 refers the tissue engineered heart valve after 14 days of pulsatile flow in a

bioreactor. The valve constructs were then implanted to same lambs and explanted at different time points.

After functioned up to 5 months histologically, mechanically and in terms of extracellular matrix formation

the autogolous tissue engineered valves resembled the normal heart valves.

Fig 6. Tissue-engineered heart valve after 14 days of pulsatile flow in a bioreactor (Hoerstrupt et al 2000)

Hoerstrup et al (2002) investigated the autologous pulmonary artery conduit tissue engineered from human

umbilical cord cells. They first harvested the human umbilical cord cells and expanded in the culture. Then

they seeded the pulmonary conduits fabricated from rapidly bioabsorbable polymers with umbilical cord

cells. They observed viable, layered tissue and stracellular matrix formation with glycosamineoglycans and

collagens. Their SEM results showed confluent, homogenous tissue surfaces. Extracellular matrix proteins

were significantly lowered compared with native tissue, and the mechanical strength of the constructs was

also comparable with native tissue. The results are given in Figures 7 and 8. Thus, they concluded that human

umbilical cord cells demonstrated excellent growth properties representing a new, readily available cell source for

tissue engineering without necessitating the sacrifice of intact vascular donor structures.

                           Fig. 7.                                                                                 Fig.8

Fig.7 Two views (A and B) of tissue engineered pulmonary artery conduit after 14 days conditioning in the

pulse duplicator bioreactor (dimensions: length, 40 mm; inner diameter, 18 mm; wall thickness, 1 mm).

Fig. 8 (A) Scanning electron microscopy of the pulsed conduits showed dense tissue formation

and a confluent smooth surface. (B) In contrast, static controls were less homogeneous. (C)

Transmission electron microscopy revealed cell elements typical of secretionally active

myofibroblasts such as collagen fibrils (asterisk) and elastin (white arrow),Hoerstrup et al 2002

Nuttelman et al (2002) developed a second generation of PVA-based scaffolds that integrates the advantages

of PVA (high water content, tissue like elasticity, and ability to attached a variety of molecules) with those of

PLA (degradability, ability to photocrosslinking and hydrophobicity). They reported that this material has

great potential as a tissue-engineering scaffold due to ability to control the rate of network degradation, mass

erosion profile and its bulk chemical properties. In their studies, valve interstitial cells were seeded on two-

dimensional surfaces of various compositions of PVA-Deg. They attributed the increased cell attachment

increased adsorption of cell adhesion proteins to hydrophobic gels.

Toshiharu et al (1995) tested the feasibility of constructing heart valve leaflets in lambs by seeding a

synthetic, polyglycolic acid fiber matrix in vivo with fibroblast and endothelial cells. They used the

following method; mixed cell populations were isolated from explanted ovine arteries. Endothelial cells were

selectively labelled with low-density lipoprotein marker and by using a fluorescent activated cell sorter; they

are separated from the fibroblast. Then they produced a tissue like sheet which was made up of a synthetic

biodegradable polymer scaffold constructed from polyglycolic acid fibers that was seeded with fibroblast.

This tissue was then seeded with endothelial cells, which formed a monolayer coating around the leaflet.

Finally, autologous and allogenic tissue engineered leaflets were implanted in seven animals. After these

experiments they concluded that tissue engineering constructed valve leaflet from its cellular components can

function in the pulmonary valve position.

Zund et al (1997) demonstrated the in vitro creation of tissue engineered heart valve tissue using

cardiovascular cells on degradable polymer matrices. They created the xenograft leaflets from human dermal

fibroblast and bovine aortic endothelial cells and the allograft valve leaflets from sheep myofibroblast and

sheep endothelial cells.

They constructed a heart valve leaflet by using a polymeric scaffold composed of polyglycolic acid (PGA)

and copolymer of polyglycolic and polylactic acid (PLA). They used two kinds of leaflets that are leaflets

constructed with a non-woven mesh and sandwich type leaflets.   Outer layer was constructed from a non-

woven mesh made from pure PGA fibers and an inner layer with a woven mesh made from a PGA

copolymer consisting of 90% PGA and 10% PLA The polymers were constructed as square sheets with a

surface area of 9 cm2.

After seeding, the xenograft constructs were examined by conventional histology and immune histology by

using markers for endothelial cells and myofibroblasts and smooth muscle cells. Similarly, after harvesting

aortic heart valve cells from lambs the tissue was serially washed with phosphate buffered saline. Under a

laminar flow hood, the tissue was minced into 1–2 mm pieces and evenly distributed in 15×60 mm tissue

culture dishes, and then gently added to the tissue culture dishes so as not to disrupt the explants. They

placed the explanted in a humidified incubator at 37°C with 5% CO2 for 6–10 weeks.  During this time

period, the cells migrated off the explants forming mixed cell populations. After the mixed cell population

had grown to confluence, the cells were labelled with an acetylated-low density lipoprotein (Ac-Dil-LDL).

These cells were then separated into LDL positive and LDL negative populations using fluorescence

activated cell sorter. The LDL negative mixed population was seeded onto the polymeric scaffold each day

over a 12-day period. This tissue-like structure was then seeded with 3×106 cells of the pure population of

endothelial (LDL positive) cells. After 14 days, conventional histology and immunhistology examined the

constructs by staining for factor VIII.

As a result they produced 40 tissue engineered heart valve leaflets (20 xenograft and 20 allograft leaflets). Microscopic examination of fibroblasts seeded on non-woven PGA mesh demonstrated that the human fibroblasts were attached to the polymeric fibers and had begun to spread out and divide (see Figure 9). At the end of the twelfth day of seeding the scaffold resembled a solid sheet of tissue. After seeding of this tissue-like structure with bovine endothelial cells, an endothelial monolayer formed on the surface of the fibroblasts. Factor VIII staining demonstrated no apparent invasion of the structure by endothelial cells nor formation of new capillary endothelial structures.

 

 Fig. 9. Formation of fibroblast-polymer bridges. This figure demonstrates polymer fiber (A) attachment of Giemsa stained fibroblast (B) and the formation of fibroblast cross bridges (C) between polymer fibers. (Zund et al 1997)

They further observed after immunohistochemical analysis of the LDL positive and LDL negative sheep

aortic-valve-cell populations that the LDL positive population stained with factor VIII resembled a pure

population of endothelial cells. After staining for actin, the LDL negative population morphologically

resembled either smooth muscle cells or myofibroblasts. They then seeded the sandwich-constructed leaflets

every other day with 106 LDL negative cells. After 12 days, the tissue-engineered constructs were seeded

with 3×106 LDL positive cells. Endothelial cells formed a monolayer on the surface of the allogenic mixed

cell population of myofibroblasts and smooth muscle cells with no apparent invasion of the structure by

endothelial cells nor formation of new capillary endothelial structures (see Figure 10). This new tissue

engineered heart valve leaflet histological resembled native valve tissue and was stronger and stiffer than the

original tissue engineered leaflets as demonstrated by physical exams.

 

Fig. 10. Immunoperoxidase staining for endothelial factor VIII on tissue engineered heart valve. Monolayer of lamb aortic valve endothelia identified by staining for factor VIII (A) on the surface of a fibroblast and smooth-muscle cell matrix (cross-section). Note neither apparent invasion of the structure by endothelial cells nor formation of new capillary endothelial structures. (Zund et al 1997)

To sum up, Zund et al demonstrated that they can successfully construct a new heart valve leaflet that has both morphological and histological similarity to a native heart valve. They further continue the functional testing of this new valve by either placing it (a) into an animal or (b) under conditions of simulated heart function (eg. bioreactor). But they argued the advantages and disadvantages of these two methods of evaluation. The advantage of an animal model is the maintenance of sterile and physiological conditions, whereas in a bioreactor long-term follow up of the tissue-engineered valve appears to be more complicated. On the other hand the bioreactor allows one to carefully control independent variables which are important for valvular development such as the pulsatile pressure, temperature, oxygen saturation, growth factors and viscosity.

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