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Publication:
Surgical Technology International XV - Cardiovascular Surgery
Article title:
Advanced Technologies for Cardiac Valvular Replacement, Transcatheter Innovations and Reconstructive Surgery

Contents:

 

 

 

 

 

 

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TECHNOLOGICAL ADVANCES

 

Technology has been striving to bring forward advances that improve the durability of bioprostheses and reduce the thrombogenicity of mechanical prostheses. The current status of technological progress is showing promise at meeting these objectives.

Bioprostheses
Glutaraldehyde has been used effectively to stabilize connective tissue for porcine and bovine pericardial heart valve substitutes during the past 25 years. Glutaraldehyde cross-linking of collagen reduces biodegradation significantly. Of the aldehydes, glutaraldehyde produces the most chemically, biologically, and thermally stable collagen cross-links. Long-term durability of glutaraldehyde-preserved bioprostheses has remained the most significant concern. Dystrophic calcification was identified initially in children and young adults. Glutaraldehyde has been implicated in the calcification process. Mechanical stress also has been implicated as a causative factor of calcification. In porcine bioprostheses, stresses were lowest at the base of the leaflet, whereas highest near the commissures where calcification is present most frequently. The highest stresses of heterograft prostheses are in the areas of greatest flexion. These observations have identified that both glutaraldehyde and mechanical stresses are of the utmost importance.
Glutaraldehyde is both a biomaterial-stabilizing agent and a sterilizing agent, but does provide a significant element of toxicity. The stabilization or tanning effect of glutaraldehyde is dependent on concentration, exposure time, temperature, pH, and concentration. The toxicity of glutaraldehyde contributes to lack of endothelial cell coverage in human implants due to aldehydes released from the treated tissue. It also is believed that the toxicity from leaching of the unbound glutaraldehyde, or its polymers from the treated tissue or aldehyde storage solutions, cause the tissue propensity to develop calcification. The heparin-based No-React® process has been reported to preserve endothelial cells and potentially inhibit calcification in implantation in children. Besides residual and unstable aldehydes, as well as mechanical stress, phospholipids are a major contributor of calcification of biological tissue. Control of phospholipids is primarily through the use of surfactants and ethanol. The new heat-process treatment of heterograft tissue removes residual and unstable aldehyde molecules by a binding process that makes the glutaraldehyde-fixed tissue unsuitable for calcification.
Alternatives to glutaraldehyde cross-linking of collagen have been pursued actively. The agents being studied either are incorporated into the tissue (eg, glutaraldehyde or epoxide), or act as promoters of the cross-linking process (eg, carbodiiamide, acyl azide, or dye-mediated photo-oxidation).
An additional method of preventing calcification of glutaraldehyde-preserved porcine tissue is preincubation with a combination of aluminum chloride and ethanol. The combination has been shown to inhibit calcification in both the cusps and aortic wall.
Dye-mediated photo-oxidation also is a promoting process of collagen cross-linking. The porcine tissue is treated with an aqueous solution, including the photo-oxidative dye and light irradiated.
Novel tissue-engineering approaches are being investigated to improve replacement heart valve durability. These tissue-engineering techniques are focused on fabricating the intricate architecture of the valve leaflets. Scaffolds have been developed from synthetic and naturally occurring polymers and then cellularized from host endothelial cells in tissue culture. Besides synthetic scaffolds, both heterograft and allograft valvular tissue can be decellularized and repopulated in vitro with the predetermined host cells. The predominant issues with this modality of tissue engineering is the maintenance of balancing scaffold disappearance and interstitial cell reseeding, and support a desirable host cellular response not susceptible to antigenic recognition and immunologic rejection.
Mechanical Prostheses
The demonstrated new standards for in vitro analysis of mechanical prostheses will likely contribute to prosthesis designs to reduce incidence of thromboembolic phenomena, including thrombosis. The flow fields within the hinge pockets of prostheses are believed to contribute to thrombus formation. Microstructural flow visualization, computational fluid dynamics modeling, laser Doppler velocimetry measurements, and laser Doppler anemometry measurements have all contributed to prostheses hinge-pocket performance and design.
These investigative technologies should be used in development of all future prosthetic designs. The likelihood exists of reduced thromboembolism and thrombosis with future prostheses and the potential for reduction of levels of anticoagulation. The only investigational prostheses that have been evaluated, formulated, or both, by these evaluative modalities are the Medtronic Advantage and On-X mechanical prostheses.

Implantation Considerations
The implantation considerations for the wide array of current developmental, as well as experimental bioprostheses and mechanical prostheses, is beyond the scope of this monograph article. Sections on implantation considerations were part of “Cardiac Valve Replacement Surgery: Prostheses and Technological Considerations” in Surgical Technology International III and “Cardiac Valvular Replacement Devices: Residual Problems and Innovative Investigative Technologies” in Surgical Technology International VI.1,2

 

CLINICAL PERFORMANCE—INDICATIONS FOR PROSTHESES TYPE

 

Cardiac valvular prostheses are evaluated by clinical and hemodynamic performance. The current-generation stented and stentless porcine and pericardial bioprostheses have, generally, satisfactory hemodynamic performance. The clinical performance is judged according to the “Guidelines for Reporting Morbidity and Mortality After Cardiac Valvular Operations”.5 The complications of cardiac valvular prostheses are structural valve deterioration, non-structural dysfunction, thromboembolism (including thrombosis), hemorrhage, and prosthetic valve endocarditis. Structural valve deterioration is the predominant complication of bioprostheses, whereas thromboembolism and hemorrhage is of mechanical prostheses.6,7
The recommended International Normalization Ratio (INR) for aortic mechanical prostheses is 2.5 to 3.0; the recommended INR for mitral mechanical prostheses is 3.0 to 3.5.7
Implantation of both mechanical prostheses and bioprostheses in the mitral position should incorporate preservation of the complete subvalvular papillary muscle-chordal apparatus to support ventricular function.8
Clinical performance of biological and mechanical prostheses at the University of British Columbia was analyzed for predictors of survival, valve-related complications, and composites of valve related complications.9-11 Evaluation disclosed a considerable preference for bioprostheses for aortic valve replacement and mechanical prostheses for mitral valve replacement.12-14
The Canadian Consensus on Surgical Management of Valvular Heart Disease has provided prostheses options for aortic valve replacement according to age range.7

 

Aortic Valve Replacement

(Table V)

Allografts and Autografts
The allograft and autograft were introduced in the 1960s as freehand subcoronary implants for aortic valve disease. The allograft has been used to manage congenital, rheumatic, degenerative, and infective disease of the aortic valve and failed bioprostheses. The major deterrent of the use of allografts is the general limited availability, shortage of donor organs, and priority for heart transplantation over allograft harvesting. Allografts provide excellent hemodynamics with low risk of endocarditis and alleviate the need for anticoagulants. The predominant indica- tions for allografts, in the current era, are children, women in childbearing age, and anticoagulant contraindications; especially in management of aortic (native and prosthetic) valve endocarditis.15-19 Currently, evidence exists from non-randomized, retrospective studies that allografts experience structural valve deterioration in a manner similar to heterografts.17,18
Autografts are usually reserved for younger patients and the active (competitive sports) patients. Early allograft degeneration appears, now, to favour autografts in children.15,17 These patients require ongoing follow up. Contraindications to the use of autografts must be respected to avoid structural failure. The contradictions are connective tissue disorders (ie, Marfan’s syndrome), immunologic disorders, and bicuspid or fenestrated pulmonary valves. The autograft has the advantage of somatic growth and, thus, is ideal in the pediatric age group. For autograft aortic root replacement, the pulmonary allograft is used for reconstruction of the right ventricular (RV) outflow tract because it is more durable than the aortic allograft.

Bioprostheses and Mechanical Prostheses
The majority of aortic valve replacements are performed in patients more than 50 years of age. The choice of valvular substitutes is based on results of two randomized trials on obsolete mechanical and heterograft prostheses,20,21 and non-randomized studies of both stand alone prosthesis types and comparative evaluations.9-11,13,14 The choice is made by balancing the complications of major thromboembolism, thrombosis, and hemorrhage with mechanical prostheses and reoperation for structural valve deterioration of bioprostheses. Currently known is that lower dose anticoagulation and self-monitored anticoagulation can make management with mechanical prostheses safer.22 Also, reoperation can be performed for structural failure of bioprostheses with low mortality, if patient surveillance can avoid emergent and New York Health Association (NYHA) class IV circumstances.23,24
Fifteen-year outcomes after replacement with both mechanical and bioprosthetic valves are reported by the Veterans Affairs randomized trial.20 At 15 years, patients who underwent AVR had better survival with a bioprosthetic valve than with a mechanical valve, even though structural valve deterioration was absent with the mechanical valve. Structural valve deterioration was greater with a bioprosthesis for AVR for patients <65 years of age than for those >65 years of age. Thromboembolism rates were similar with the two valve prostheses, but bleeding was more common with the mechanical prosthesis.
The Edinburgh randomized trial reported in 2003 results to 20 years.21 The prosthesis type did not influence survival, thromboembolism, or endocarditis. Major bleeding was more common with mechanical prosthesis. Assessing mortality and reoperation, survival with original prosthesis became different at 8-10 years for MVR and 12-14 years for AVR.
Sufficient evidence exists to recommend bioprostheses, porcine or pericardial, for patients at least 65 years of age. The evidence pertains to both first- and second-generation heterograft stented bioprostheses.6,7,9,10,14,25
The mechanical prostheses currently marketed are free from structural failure.
Stentless bioprostheses have been shown to have better hemodynamics in non-randomized studies than stented bioprostheses and mechanical prostheses.26,27 The stentless design may increase long-term freedom from structural valve degeneration and potentially improve survival. The potential improvement in survival is considered to be related to completeness of left ventricular mass regression and remodeling. Several studies have reported that both stented and stentless bioprostheses achieve adequacy of left ventricular mass regression even though stentless bioprostheses can provide lower transvalvular gradients and better effective orifice area indices.26-28 It is apparent that mild-to-moderate obstructive phenomena do not influence mass regression and survival.
The use of small size prostheses is controversial. Evidence exists of significant residual gradients with valve sizes 19 and 21 with the majority of stented bioprostheses and mechanical prostheses. The sewing cuff configurations of small aortic mechanical prostheses, external mounted pericardial bioprosthesis, and advanced supra-annular pericardial and porcine bioprostheses have been designed to address these issues. The stentless bioprostheses also address this issue.

Aortic Valve Substitutes
The optimization of hemodynamic performance of valvular substitutes in aortic valve replacement has always been recognized as being of extreme importance. The important objective of aortic valve replacement is to minimize postoperative gradients and optimize the normalization of left ventricular mass and function. The most frequent cause of high postoperative gradients occurs when the effective prosthetic valve area is less than that of the normal human valve; known as patient-prosthesis mismatch, even in the presence of normally functioning valve prostheses. Patient-prosthesis mismatch occurs when the size of the prosthesis orifice is too small for the basal-surface area of the patient; ie, the relationship of prosthesis size and body size. The effective orifice area index, as a measure of patient-prosthesis mismatch, should not be less than 0.85cm2/m2 to avoid significant gradients at rest and exercise.29,30 Higher gradients usually occur when the prosthesis size is <21 mm. Increased transvalvular gradients occur with, and cause, reduced effective orifice areas and compromise regression of the left ventricular mass.
The normally functioning standard stented bioprostheses are obstructive, by nature, with non-physiologic flow patterns and residual pressure gradients. The stentless bioprostheses provide laminar, non-obstructive flow, even though implanted intra-annularly with the prosthesis having a relatively smaller internal diameter for the same label size, not considering the upsizing often achieved.
The importance of optimal hemodynamic performance with low gradients, satisfactory effective orifice areas, and normalization of ventricular muscle mass has been evaluated extensively in recent years. Left ventricular hypertrophy is the physiological response to increased afterload, pressure overload, or both. The clinical phenomenon of pressure overload is aortic stenosis, whereas increased afterload is systemic hypertension. Aortic valve replacement facilitates left ventricular mass regression and left ventricular remodelling. Left ventricular mass regression is dependent on changes in gradients and changes in effective orifice areas. Left ventricular mass regression commences immediately after aortic valve replacement and is completed by six months. The major factors that influence left ventricular mass are baseline left ventricular mass and patient-prosthesis mismatch.
The influence of optimal hemodynamics during rest and exercise and consequently prosthesis type has been addressed. Stentless bioprostheses from non-randomized studies have been shown to have better hemodynamics than stented bioprosthesis.26,27 However, two randomized trials have reported that no detectable significant differences exist with regard to hemodynamic performance and regression of left ventricular mass from stentless porcine bioprostheses and current-generation pericardial bioprosthesis.31,32 The higher incidence of patient-prosthesis mismatch with stented bioprostheses in the small aortic root is reported from non-randomized studies. Evidence exists that left ventricular mass regression may occur even with levels of patient-prostheses mismatch. Some evidence has been reported that stentless bioprostheses in non-randomized studies provide advanced survival over stented bioprostheses. The survival advantage occurs in patients <70 years of age, but not in patients >70 years of age.28 This may be related to less than adequate regression of left ventricular mass, due to patient-prosthesis mismatch being of lesser significance in patients with more sedentary, less-active lifestyles. The issue of durability of stentless porcine bioprostheses compared to stented bioprostheses remains unresolved and is unlikely to be determined until the evaluation period is extended to 10-12 years.
The cardiac surgeon should address the optimization of hemodynamic performance in aortic valve replacement surgery. The choice of indexed effective orifice area is believed to be the minimal requirement for a given patient, with the knowledge that 0.85 cm2/m2 or higher is the optimal value for better hemodynamics.29,30
The Canadian investigators from Laval University have proposed a simple three-step algorithm that can be performed easily in the Operating Room to prevent patient-prosthesis mismatch.29,30 The minimal effective orifice area (EOA) values are related to the patient basal surface area (BSA) to facilitate delineation of indexed EOA of three levels (>0.85 cm2/m2, >0.80 cm2/m2, and >0.75 cm2/m2). These investigators have determined that the ideal effective orifice area index (EOAI) should be >0.85 cm2/m2. The normal in vitro and in vivo effective orifice areas for the most commonly used prosthetic valves can be made available to surgeons and hospital Operating Rooms.
The following three-step algorithms can easily be performed in the Operating Room: 1) Calculate the patient’s BSA from weight and height using the Dubois equation. 2) From the table, determine the minimal valve EOA required to ensure an indexed of EOA >0.85, >0.80, or 0.75 cm2/m2. The choice of EOAI is deemed to be the minimal requirement for a given patient, with the knowledge that 0.85 cm2/m2 or higher is the optimal value for better hemodynamics. 3) Select the type and size of prosthesis that has reference values for EOA greater or equal to the minimal EOA value obtained in Step (2) above.
The reference values provided by the manufacturers, and/or published by investigators, may be in vivo or in vitro values. In vitro values derived from pre-marketing studies usually overestimate in vivo values by 10% to 15%, but otherwise correlate well with in vivo values. A notable exception is stentless valves in vitro values for EOA grossly overestimate in vivo values and, therefore, cannot be relied upon. The in vivo EOA values for bileaflet valves may artifactually be underestimated by Doppler echocardiography, so a value for EOA lower than the reference value does not necessarily mean prosthesis dysfunction. Manufacturers should provide both in vitro and in vivo values to assist surgeons in minimizing patient-prosthesis mismatch.

Mitral Valve Replacement (MVR)

The choice of prosthesis is again a decision to be made by the surgeon and the patient, with full knowledge of the advantages and disadvantages of the different types available. The patient must be informed that the valve replacement is only an alternative to valve reconstruction. Bioprostheses have a limited role in MVR because of the increased evidence of structural valve deterioration compared with their use for AVR.6 Bioprostheses are indicated in patients >70 years of age and those with comorbidity and anticipated reduced life expectancy.
The outcomes 15 years after valve replacement with mechanical versus bioprosthetic valves have been reported by the Veterans Affairs randomized trial.20 All-cause mortality was not different after MVR with mechanical prostheses versus bioprostheses. Structural valve deterioration was greater with bioprostheses for MVR in all age groups, but occurred at a much higher rate in those aged <65 years. Thromboembolism rates were similar in the two valve prostheses, but bleeding was more common with the mechanical prostheses.
The Edinburgh randomized trial reported results to 20 years in 2003. The prosthesis type did not influence survival, thromboembolism, or endocarditis.21 Major bleeding was more common with mechanical prosthesis. Assessing mortality and reoperation, survival with original prosthesis became different at 8-10 years for MVR and 12-14 years for AVR.
The newer-generation mechanical prostheses designs with hinge mechanisms to reduce stasis may facilitate control of thromboembolic phenomena with low-dose anticoagulation to reduce the risk of hemorrhage.

SUMMARY OF EXPERIENCE—UNIVERSITY OF BRITISH COLUMBIA

 

The predominant concerns of patients who undergo valve replacement surgery are risks of stroke, antithrombotic bleeding, and reoperation related to the replacement prosthesis. Recent reports from the University of British Columbia and affiliated teaching hospitals have compared composites of valve related complications—valve related reoperation, valve related morbidity (permanent impairment), and valve related mortality between bioprostheses and mechanical prostheses for both MVR and AVR. The patient’s concerns in making a choice of prosthesis are the risks of death related to the prosthesis, stroke or bleeding that cause permanent impairment, and the risk of reoperation.
There has been a worldwide trend of increased implantation of bioprostheses over mechanical prostheses, more prominent in North America than Western Europe (Fig. 105). This trend is especially evident for aortic valve replacement. Surgery for mitral valve disease should be dominated by mitral valve reconstruction and, if not appropriate, mechanical prostheses or bioprostheses.
The experience from the University of British Columbia with the Carpentier-Edwards supra-annular porcine bioprosthesis is the longest series of any currently marketed porcine and pericardial aortic bioprosthesis.25 The reported series included 1,823 patients who underwent 1,847 procedures between 1981 through 1999. The two accompanying figures demonstrate both the actuarial and actual freedom from structural valve deterioration for the overall population (mean age: 68.9 years) and age groups (<50, 51-60, 61-70, and >70 years) to 15 and 18 years (Figs. 106 & 107). The predictors of structural valve deterioration were age (HR 0.96, p<0.01), male gender (HR 1.75, p=0.0255), and concomitant coronary-artery bypass (HR 0.58, p=0.0256). Structural valve deterioration is the predominant valve related complication of bioprosthesis that necessitates reoperation. The CE-SAV can be considered the “gold standard” of clinical performance to which other second- and third-generation bioprostheses can be compared.
The clinical performance of bioprostheses and mechanical prostheses implanted between 1982 and 1998 were evaluated to 15 years for predictors and freedom from composites of valve related complications for both MVR and AVR.9,10
The study was conducted for AVR of bioprostheses and mechanical prostheses implanted between 1982 and 1998 that assessed predictors of performance and composites of valve related complications (BP-2,178 patients, 2,195 procedures; MP-883 patients, 980 prostheses) (Tables VIa & VIb). The same study was conducted for MVR between 1982 and 1998 (BP-943 patients, 959 procedures; MP-839 patients, 961 prostheses) (Tables VIIa & VIIb).