Advanced Search

Doty DB, Doty JR. Stentless Aortic Valve Replacement: Bioprostheses.
In: Cohn LH, Edmunds LH Jr, eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003:889898.

This Article
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this book
Right arrow Author home page(s):
Donald B. Doty
John R. Doty
Google Scholar
Right arrow Articles by Doty, D. B.
Right arrow Articles by Doty, J. R.
Right arrow Articles citing this Article
Right arrow Search for Related Content
PubMed
Right arrow Articles by Doty, D. B.
Right arrow Articles by Doty, J. R.
Related Collections
Right arrow Valve disease

Chapter 35

Stentless Aortic Valve Replacement: Bioprostheses

Donald B. Doty/ John R. Doty

STENTLESS AORTIC BIOPROSTHESES
????St. Jude Medical Toronto SPV
????Medtronic Freestyle Aortic Root Bioprosthesis
????Edwards Lifesciences Prima Plus
????CryoLife-O'Brien
????AorTech Freesewn Porcine Elan
????Shelhigh No-React Stentless Bioprosthesis
????Biocor PSB/SJM
????Sorin Pericarbon Stentless Bioprosthesis
OPERATIVE TECHNIQUE
????Subcoronary Valve Replacement
????Root Inclusion
????Root Replacement
CLINICAL RESULTS
????Hemodynamic Performance
????Echocardiographic Functional Assessment
COMPLICATIONS
????Reoperation for Valve Explant
????Thromboembolism
????Endocarditis
????Structural Deterioration
SURVIVAL
CHOOSING A BIOPROSTHESIS
CONCLUSION
REFERENCES

?? INTRODUCTION
 Top
 Next
 References
?
After nearly 40 years of experience with bioprosthetic heart valves, it would seem reasonable that a single design of bioprosthesis, ideal for all circumstances in which it is necessary to replace the aortic valve, should have emerged. Unfortunately, this is not the case. The surgeon must choose from an ever-increasing number of replacement devices. There seems to be no end to the new devices that are being designed, tested, and added to the market availability after short-term clinical trials. By the time medium-term or in some cases long-term performance data are known, an equal number of valves have been discarded in favor of new and unproven devices.

The porcine aortic valve, directly implanted into the aortic root, was originally proposed for aortic valve replacement by Binet et al in 1965.1 O'Brien subsequently developed a heterograft valve bank for continued use of both bovine and porcine nonstented valves.2 Direct heterograft valve implantation was abandoned because of unsatisfactory results, likely due to inadequate tissue preservation, in favor of heterograft valves that were mounted on a stent frame. Stented bioprostheses manufactured to provide a standard device that is easily implanted and provide reproducible results in the aortic position were associated with good short- and medium-term results. Unfortunately, stented heterograft tissue failure with calcification and cusp rupture became apparent with longer follow-up, particularly in younger patients. Hemodynamic performance of stent-mounted porcine valves was less than ideal when the aortic root was small.

David et al revived the concept of direct insertion of a nonstented porcine heterograft into the aortic root in 1990.3 This valve, originally manufactured on a limited trial basis by Hancock Laboratory, was subsequently produced for clinical use by St. Jude Medical as the Toronto SPV (stentless porcine valve). Other devices were developed soon thereafter.

The search for the ideal prosthesis for aortic valve replacement continues, and recent advances in tissue valve technology have engineered the development of a new generation of stentless bioprosthetic valves. Traditionally, bioprosthetic valves are mounted on a semirigid stent, which maintains the valve geometry and assists the surgeon in implanting the valve. The new stentless xenograft valves do not have these prosthetic stents, allowing for larger valves to be implanted with presumably better hemodynamic performance than if a stented bioprosthesis is used.


?? STENTLESS AORTIC BIOPROSTHESES
 Top
 Previous
 Next
 References
?
A partial listing of commercially available stentless aortic bioprostheses follows. Some are available in the United States and others are available only in international markets. Three basic techniques are used for implantation depending on the construction of the stentless bioprostheses: (1) subcoronary valve replacement; (2) root inclusion; and (3) root replacement.

St. Jude Medical Toronto SPV

This device (from St. Jude Medical, St. Paul, MN) is derived from the porcine aortic root. The porcine tissue is fixed in glutaraldehyde with the aortic valve in the closed position by applying low pressure to the fixative solution. No anticalcification agent is added. The aorta is removed from all three sinuses of Valsalva and the exterior is covered completely with fine polyester fabric. The device is used for aortic valve replacement only as a subcoronary implant in the essentially normal aortic root without dilation of the sinotubular junction. Modifications of the device are planned to offer a full aortic root and to add BioLinx anticalcification treatment to the bioprosthesis.4 The anticalcification agents include treatment of the aortic wall with aluminum chloride (AlCl3) and curing the aortic leaflets with ethanol.

Medtronic Freestyle Aortic Root Bioprosthesis

This valve (from Medtronic, Minneapolis, MN) is a stentless valve derived from a porcine aortic root preserved in glutaraldehyde and has a ring of polyester at the inflow and covering the septal myocardium, which provides strength and ease of implantation. The Freestyle device is presented as an intact porcine aortic root with ligated coronary arteries. The aortic root is preserved in a buffered 0.2% glutaraldehyde solution to which an antimineralization agent, alpha amino oleic acid, has been added. Zero net pressure is applied to the valve leaflets while the aortic root contour is maintained in a slightly dilated position by applying a pressure of 40 mm Hg to the intra-aortic solution. This process is designed to retard calcium deposition5,6 and retain the natural collagen crimp and flexibility7 in the valve leaflets. The device may be implanted as a subcoronary valve replacement, as an inclusion root, or as an aortic root replacement.

Edwards Lifesciences Prima Plus

This prosthesis (from Edwards Lifesciences, Irvine, CA) consists of an extended porcine aortic root fixed in glutaraldehyde at low pressure. The "Plus" designation indicates treatment with the proprietary XenoLogiX FET-80, a combination of agents including ethanol and Tween-80 (surfactant) to retard calcification.8 A minimum of polyester fabric is used to enhance pliability. There are markings on the outside of the aortic root to guide trimming of the aorta. It can be implanted subcoronary, as an inclusion root, or as an aortic root replacement.

CryoLife-O'Brien

This stentless porcine aortic valve (from CryoLife, Inc., Kennesaw, GA) is a manufactured composite of the noncoronary sinus and leaflet from three porcine aortic roots. It is fixed in glutaraldehyde at low pressure without calcium retardant. The bioprosthesis has no polyester cloth support and the only synthetic material is the suture that holds the leaflets together. It is designed to be implanted below the coronary arteries in a supra-annular position in the sinuses of Valsalva by a single suture line. Experience is limited to a few centers and the technical aspects of implantation appear to be somewhat more difficult than the other stentless bioprostheses in spite of only a single suture line being employed.

AorTech Freesewn Porcine Elan

This porcine aortic valve (from AorTech, Bellshill, Scotland, UK) is fixed at low pressure in glutaraldehyde and is designed for subcoronary implantation as a valve replacement. The aorta from all three sinuses of Valsalva is removed and a cuff of pericardium is attached to the inflow tract. A valve holding device is supplied.

Shelhigh No-React Stentless Bioprosthesis

This prosthesis (from Shelhigh Inc., Millburn NJ) is a porcine aortic valve or aortic root fixed in glutaraldehyde at low pressure. The tissue is "skeletonized" and covered with fixed pericardium for support. No-React9,10 is a proprietary surfactant/heparin binding chemical process. The device is implanted in the subcoronary position.

Biocor PSB/SJM

This heterograft (from Biocor Industria e Pesquisa Ltda, Belo Horizonte, MG, Brazil) was originally developed in Brazil and is a composite valve constructed from three individual porcine leaflets fixed at zero pressure in glutaraldehyde. Now marketed by St. Jude Medical, the prosthesis is treated with the proprietary No-React9,10 surfactant treatment to reduce calcification. The leaflets are secured to a strip of bovine pericardium to create a slightly conical conduit. Subcoronary implantation is employed.

Sorin Pericarbon Stentless Bioprosthesis

This is a stentless all-bovine pericardial valve (from Sorin Biomedica, Saluggia, Italy). A glutaraldehyde-fixed sheet of bovine pericardium is formed into a valve that is supported by a second sheet of bovine pericardium attached using pyrolite carbon-coated suture. This device is implanted as an aortic valve replacement in the subcoronary position, tailoring the patient noncoronary sinus to reduce the diameter of the sinotubular junction for a discrepancy of less than 10% compared with the annular diameter.11


?? OPERATIVE TECHNIQUE
 Top
 Previous
 Next
 References
?
Subcoronary Valve Replacement

In this technique the bioprosthesis is used only as a valve supported by the sinus aorta of the patient.1118 A transverse aortotomy is made 5 to 10 mm above the sinus rim. Alternatively, the ascending aorta is transected for exposure of the aortic root and coronary arteries. The diseased aortic valve is excised and calcium depositions are thoroughly debrided from the aortic root. The diameter of the aortic root is measured at the ventriculoaortic junction (valve annulus) using obturators provided by the manufacturer. The diameter at the sinotubular junction is measured when the Toronto SPV valve is considered for implantation. Major dilation of the sinotubular junction contraindicates use of this bioprosthesis but not the use of the Freestyle device. An equal or slightly larger diameter size of the bioprosthesis is selected for implantation. Associated procedures are performed while the bioprosthesis is rinsed in saline solution to remove glutaraldehyde.

The Toronto SPV, CryoLife-O'Brien, Shelhigh, AorTec, Biocor, and Sorin devices are pretrimmed and ready for implantation. The Freestyle and Prima Plus valve must be tailored by removing the sinus aorta from the right and left coronary sinuses of the bioprosthesis. The noncoronary sinus is usually left intact so that the position and spatial relationships of the commissures on either side of the noncoronary sinus are fixed, making implantation more reproducible. The bioprosthesis is implanted in anatomic position without rotation unless the right coronary artery is positioned so low that the prosthesis will not fit under it. The prosthesis could be rotated 120 degrees in that situation to place the right coronary sinus of the graft into the noncoronary sinus of the patient.

The cloth sewing rim at the inflow margin of the graft is attached to the patient aortic root using continuous or interrupted suture technique. The suture line is kept in a level plane through the lowest points of the dense fibrous tissue of the hinge of the native valve (annulus). The suture line is below the annulus in the interleaflet triangle except in the region of the membranous septum, where the suture line must follow the annulus directly in order to protect the conduction system from injury. During suture placement, the bioprosthesis is held away from the native root because it is too stiff to work with conveniently when lowered into the aortic root. The exception is the Sorin Pericarbon Stentless Bioprosthesis, which is flexible enough to be inverted into the left ventricular outflow tract during proximal suture line placement.11

When all of the stitches are placed, the graft is attached to the aortic root by lowering it into place and adjusting suture loop tension on continuous suture or tying down interrupted stitches. The sinus aorta of the graft is attached to the sinus aorta of the patient below the coronary arteries. When the Toronto SPV or the other fully trimmed devices are used, the sinus aorta must also be contoured into the noncoronary sinus of Valsalva. Continuous stitches of polypropylene suture are placed in radial fashion below the coronary artery ostium. The stitches are often quite close to the ostium because the cloth covering on the graft raises the graft. This position of the graft cannot be forced to a lower position without risking graft buckling. The suture line is carried to the top of both adjacent commissures. When the noncoronary sinus remains intact, the position of two of the commissures is fixed so that proper location of the commissure between the right and left coronary sinuses ensures a competent valve. The preservation characteristics of the bioprostheses aid in proper implantation, because even the trimmed graft aorta holds its shape well. This also holds for grafts in which all three sinuses have been removed. The patient aorta may be conformed and approximated to the aorta of the graft in reproducible fashion. The noncoronary sinus of the patient may be closed over the graft as there is sufficient space to accommodate the graft without distortion. The graft is trimmed above the sinotubular junction (sinus rim) and approximated to the inside of the closed aorta of the patient or to the cut edge of the divided aorta. If the aorta has been divided, it is reanastomosed in end-to-end fashion. Valve function is checked by intraoperative echocardiography in all cases.

Root Inclusion

Root inclusion technique refers to placement of the Freestyle or Prima Plus bioprosthesis as a tube inside the native aorta.19 This technique is performed least frequently and may be more difficult than the other techniques. It is done in an attempt to reduce the possibility of distortion of the graft. The only modification to the graft is openings made in the sinus aorta to accommodate anastomosis of the patient coronary arteries to the graft. This technique is useful for a patient with a dilated aortic root and ascending aorta that is not aneurysmal.

A transverse incision of about two thirds of the aortic circumference is made in the ascending aorta about 4 cm above the annulus. The aorta may also be divided completely to obtain better exposure of the aortic root. The aortic valve is excised and the annulus debrided of all calcareous deposits. The size of the annulus is measured as described above. An appropriate size bioprosthesis is chosen and rinsed. The aorta in the right and left sinus of the graft is completely excised from just below the sinotubular junction to the cloth covering below. Continuous stitches of monofilament suture are used to attach the inflow sewing ring of the graft to the left ventricular outflow tract at a level plane at the level of the annulus. The three commissures of the bioprosthesis are then aligned within the aortic root by placing separate mattress sutures from the graft to an appropriate position above the commissures of the patient through the aortic wall. The sinus aorta of the graft is attached to the sinus aorta of the patient by continuous suture working from within the graft. The position of the sutures is governed by the appropriate anatomic fit of the graft to the aortic root. The distal end of the graft is shortened to approximate the aortic incision. The graft is incorporated into the aorta by continuous suture taking up excess patient aorta to the graft. The aortotomy is closed or the aorta reanastomosed. Valve function is checked by intraoperative echocardiography.

Root Replacement

Root replacement means that the entire native aortic root and valve are excised and replaced with the Freestyle or Prima Plus bioprosthesis.20 Full-root replacement technique is employed for the treatment of aortic root pathology that precludes the use of other techniques that require relatively normal patient aorta to support the graft. It is also employed because there is the least chance for aortic valve distortion of any of the implant techniques. Full-root replacement technique is possible only with the Freestyle and the Prima Plus devices.

The aorta is divided above the sinotubular junction. Both coronary ostia are mobilized on generous buttons of aortic wall. The remaining sinus aorta is removed. The aortic valve is excised and the annulus debrided. The size of the annulus is measured and an appropriate size valve is chosen. A larger prosthesis may be employed because the device will stand by itself and is not enclosed within the aorta. The inflow sewing ring of the graft is attached to the aortic annulus with multiple interrupted stitches of 3-0 braided polyester suture or a continuous stitch of 3-0 polypropylene suture. It is important to line up the position of the left coronary artery of the graft with the left coronary artery of the patient during construction of the proximal suture line. The left coronary ostia of the graft is opened and an anastomosis of the left coronary artery made to the graft using continuous stitches of 5-0 polypropylene suture. Location of the proper position for the right coronary anastomosis is aided by filling the right ventricle. The right coronary artery ostium of the graft is opened if it is properly positioned, or another opening is made in the right coronary sinus. The right coronary artery is anastomosed to the graft. An end-to-end anastomosis of the distal end of the graft is constructed to the ascending aorta. It is usually necessary to make some size adjustment of the patient aorta or the graft to achieve a good fitting anastomosis. In some cases, the graft is extended with a polyester graft for replacement of the ascending aorta. Intraoperative echocardiography is performed to assess aortic valve function and segmental left ventricular wall motion. Abnormal left ventricular wall motion or ventricular arrhythmia suggests coronary artery blood flow compromise, which should be treated by reconstruction of coronary artery-to-graft anastomoses or by coronary artery bypass grafts.


?? CLINICAL RESULTS
 Top
 Previous
 Next
 References
?
Several authors have now reported large series with mid-term follow-up on the Medtronic Freestyle and the Toronto SPV valves.12,2134 There is less experience with the other valves.3543 Mid-term (5-year) studies have shown excellent performance for all devices. Early mortality is low and comparable to mechanical or stented bioprostheses. Freedom from valve-related mortality is low with the stentless xenografts, although there has not been sufficient long-term follow-up to identify late hazards or associated risk factors. The Toronto SPV bioprosthesis and the Medtronic Freestyle aortic root bioprosthesis have been implanted in a large number of patients, mostly over the age of 61 years. Follow-up extends to 10 years for the Toronto SPV valve12 and over 7 years in some patients with the Freeestyle valve.21,22 Investigators have compared these two stentless bioprostheses in single-institution trials and have found very little difference in hemodynamic or clinical results. Del Rizzo and Abdoh44 found no differences in clinical outcome or hemodynamic performance between these two valves and both devices offer excellent results with normalization of left ventricular function. Legare et al45 reported that the hemodynamic performance of both valves was excellent and equivalent, but there was slightly more aortic valve regurgitation with the Toronto SPV valve. Bach et al46 recently presented data suggesting increased aortic valve regurgitation at 8 years after operation using the Toronto SPV valve, which may be attributed to dilation of the unsupported sinotubular junction. At mid-term follow-up, however, there seems to be little difference in clinical results for the two valves.

There was an acceptable risk of operation in the Freestyle experience (5.7% overall), considering that most of the patients were elderly.21 The aortic valve lesion for which aortic valve replacement was required was pure stenosis in 43% or mixed stenosis and insufficiency in 45% (total stenotic lesions = 88%). There was a remarkable improvement in functional capacity after operation with 95% of patients in functional class I or II; 73% had been in class III or IV prior to operation.

The most popular method of implantation has been subcoronary valve replacement.21 Although this method requires knowledge of the spatial relationships of the aortic root, it does not alter the natural tissues of the aortic root substantially. In that sense, it is somewhat less of an operation than aortic root replacement techniques, but in another sense, it may be more difficult to perform reproducibly. The data from the Freestyle series22 show that there is remarkably high probability (95% to 100%) that the bioprosthetic valve will be competent or have no more than mild regurgitation regardless of the technique chosen for implantation. Risk of hemorrhage may be less and it may be more easily controlled with subcoronary valve replacement or root inclusion technique than with full-root replacement technique because the bioprosthesis is completely enclosed within the natural aorta so that the only source of major bleeding is the readily accessible aortotomy. Risk of operation was lowest using subcoronary valve implant techniques (5.0% vs. 9.3% for full root), even though the patients were older with two thirds being over the age of 70 years.21 Subcoronary technique also required less myocardial ischemia time by about 20 minutes compared to the aortic root techniques.21 Less xenograft aorta is inserted when the subcoronary valve replacement is used and may account for a somewhat less frequency of thromboembolism. Xenograft aorta will ultimately calcify even though anticalcification agents are added to the fixative because retardation of calcification in the aorta is less effective than in the leaflet tissue. The possible exception may be the use of BioLinx technology,4 because AlCl3 appears to be more effective than other agents in inhibiting aortic calcification. This may also be in favor of using a subcoronary valve implantation technique so that more of the patient's own flexible aorta is preserved. On the other hand, the most perfect early and late implants in terms of valve competence were achieved by full-root replacement technique.

Aortic root pathology encountered at operation surely affected choice of operation.22 Aortic root pathology often dictates replacement of the aortic root or ascending aorta, favoring full-root replacement compared to the other techniques in which the bioprosthesis is enclosed within the aortic root. Aortic root replacement operations, however, require more time to perform by about 20 to 30 minutes. This was especially important when aortic valve replacement was accompanied by aortocoronary bypass. Taken in sum, a longer procedure, more complex aortic root pathology, and more exposed suture lines in complete aortic root replacement procedures may extract a higher early death rate after operation than when other methods are employed. By 7 years, however, actuarial analysis22 indicates little difference in survival when subcoronary implant technique is compared to full-root technique (62.0% vs. 67.7% freedom from death).

Hemodynamic Performance

The remarkable functional improvement may be related to excellent hemodynamic performance of the stentless bioprosthesis. These xenografts have very favorable hemodynamic performance, even in the smallest sizes, and are therefore ideally suited for the patient with a small aortic root.47,48 By eliminating the stent, a larger valve can be implanted in the patient's aortic root. Mean systolic gradients are low, generally less than 10 mm Hg. Mean gradients across the various sizes of the Medtronic Freestyle valve22 have shown about 15 mm Hg for 19-mm bioprostheses, with the larger valves having lower mean transvalvular gradients. These gradients approach those of homograft valves, which are only slightly higher than the normal aortic valve. Low transvalvular gradients were sustained during mid-term follow-up. Over the first several months after implantation of a stentless heterograft, effective valve orifice area actually increases and there is measurable regression in left ventricular hypertrophy as the left ventricle undergoes remodeling with improved function.4953 In general, a 10% to 20% reduction in left ventricular mass occurs over the first 6 to 12 months and stabilizes at that point. In a prospective, randomized study Walther et al54 found a greater regression of left ventricular hypertrophy in patients receiving stentless bioprostheses compared to other types of valve prostheses. Maselli et al55 and Jin et al56 both reported a more rapid and complete resolution of left ventricular hypertrophy and greater improvement in left ventricular function when either aortic homograft or a stentless porcine bioprosthesis was used for aortic valve replacement as compared to stented bioprostheses or mechanical valves. A previously reported reduction in transvalvular gradient observed in the first year after operation stabilized and remained constant up to the 4-year mark.21 Effective valve area has been consistently good even in small size valves allowing implantation of 19-mm or 21-mm prostheses without enlargement of the aortic root with expectation that hemodynamic performance will be good.16 Low transvalvular gradient and large effective orifice area even in 19-mm and 21-mm valves reduce the possibility of patient-to-prosthesis size mismatch and are associated with rapid resolution of left ventricular hypertrophy.

Echocardiographic Functional Assessment

The absence of a sewing ring and stents on the new stentless bioprosthesis results in an echocardiographic image that is very similar to the native aortic valve. There are, however, some important characteristics of a stentless bioprosthesis that should be evaluated with intraoperative transesophageal echocardiography during the initial implantation and subsequently with either transesophageal or transthoracic echocardiography during follow-up.

Evaluation of global left ventricular function either in the preoperative setting or by transesophageal echocardiography in the operating room prior to the initiation of cardiopulmonary bypass is important to determine overall and segmental left ventricular function. Reduced left ventricular function prior to the ischemic period required for aortic valve replacement may affect the choice of operation, favoring more simplified approaches. Intraoperative imaging should also assess the status of the left ventricular outflow tract including subvalvular obstruction, associated valvular heart disease, and the condition of the aortic root and ascending aorta.

The stentless bioprosthesis should be assessed after implantation and separation from cardiopulmonary bypass, but before administration of protamine, to examine for the presence and degree of valve regurgitation as well as to establish a baseline for the specific anatomic characteristics of that valve. The stentless bioprosthesis should be carefully evaluated with intraoperative echocardiography for the presence of paravalvular leak. Bach57 has extensively described the variants in paravalvular anatomy with these valves, noting that there is creation of a potential space between the native aortic wall and the porcine aortic wall. The size, extent, and echo characteristics of this potential space vary depending on the specific bioprosthesis and how much of the porcine root is actually inside the native aortic root. Valves that are implanted using the subcoronary technique have the smallest amount of tissue overlap, while root inclusion techniques produce the greatest amount. This tissue overlap results in a "double lumen" appearance that gradually resolves over time, with near-complete resolution at 6 months as demonstrated by Bauer et al.58 Accumulation of fluid and hematoma in the space between the graft and the aorta results in an echo-lucent area. These collections should be carefully interrogated with color flow Doppler to assess the presence of diastolic flow, which indicates a paravalvular leak. It is difficult to determine the precise origin of such leaks, but paravalvular leaks always originate at the distal suture line, above the prosthetic valve. The stentless bioprostheses, with the exception of the Cryolife-O'Brien valve, all require both a proximal and distal suture line. A paravalvular leak can be demonstrated either by the presence of diastolic flow between the porcine wall and the native aortic wall or at the level of the annulus. Both findings are indicative of valve dehiscence at the distal suture line and are an indication for resumption of cardiopulmonary bypass and revision of the distal suture line. If there is no evidence of paravalvular leak and valve function is otherwise normal, paravalvular edema and/or hematoma do not require intervention.

Stentless bioprostheses can be inserted with a high degree of diastolic competence. In one study, the bioprosthesis was competent or only mildly incompetent in 96% to 100% of the patients, with the highest levels of competence achieved when the device was implanted by the full-root replacement technique.22 Moderate valve regurgitation was present in only 8% of patients at the 6-year mark and there were no patients with severe valve regurgitation. The Sorin Pericarbon device showed somewhat higher incidence of aortic valve regurgitation11 with 69% having no regurgitation, 23% mild, and 8% moderate regurgitation.


?? COMPLICATIONS
 Top
 Previous
 Next
 References
?
Reoperation for Valve Explant

Eight valves were explanted in the Freestyle series22 for technical problems resulting in valvular incompetence or unsatisfactory hemodynamic performance. This is a very low incidence of valve explantation, indicating that surgeons can master the techniques of insertion and become confident that this bioprosthesis will have good hemodynamic performance and will not leak. An additional 6 valves were explanted for infective endocarditis. None were removed for structural deterioration of the bioprosthesis. Total valve explant rate was 0.5% per patient-year, leaving 92% to 99% of patients free of valve explant at the 7-year mark.

Thromboembolism

Thromboembolic rate for the Freestyle bioprosthesis was low,22 in spite of the fact that patients were not given warfarin unless there was persistent atrial fibrillation or flutter. Early thromboembolism was noted in only 1.9% of patients having subcoronary valve implantation when very rigid criteria were applied. Late thromboembolism occurred at a rate of 1.6 events per patient-year, with permanent neurologic events at an even lower rate of 0.6 per patient-year. Actuarial analysis of thromboembolism rate showed 78% to 87% of patients free of this complication at 7 years after valve implantation.

Endocarditis

Endocarditis was an infrequent event in the Freestyle experience.22 The freedom from endocarditis was greater than 94.5% at 7 years. This indicates that the Freestyle bioprosthesis is quite resistant to infection, and that infection on this bioprosthesis can be treated and cured. Endocarditis, however, accounted for nearly one half of the valves that were explanted (6 of 14).

Structural Deterioration

Structural deterioration during the 5-year follow-up has been rare,21 with no valves explanted for this cause. These data imply that if the Freestyle bioprosthesis can be implanted with technical accuracy and without bacterial contamination, it can be expected to function very well up to the 7-year mark. It is too early to know if the durability of the Freestyle bioprosthesis will compare favorably with other bioprostheses. The hope and expectation are that the zero-net pressure fixation of the porcine aortic valve leaflets and the addition of alpha amino oleic acid to the tissues, technology unique to this bioprosthesis, will favorably affect durability, but many more years of detailed follow-up are needed before this can be known.


?? SURVIVAL
 Top
 Previous
 Next
 References
?
There is increasing evidence of the hemodynamic benefits of the stentless bioprostheses. Retrospective data suggest improved survival compared to standard aortic valve replacement with either mechanical or stented bioprostheses.54,59,60 This could be related to improved hemodynamics and/or resolution of left ventricular hypertrophy. Del Rizzo et al60 reported on over 1100 patients undergoing stentless aortic valve replacement, and documented that baseline left ventricular mass index and patient-prosthetic mismatch have significant effects on the regression of left ventricular hypertrophy. For a given body mass index, there is a predicted normal size for the aortic annulus. Patient-prosthesis mismatch is defined as a postoperative indexed valve effective orifice area of less than or equal to 0.85 cm2/m2, as described by Pibarot et al.61 Inserting a prosthesis that is smaller than the predicted normal size produces patient-prosthesis mismatch, which can result in higher transvalvular gradients and left ventricular outflow obstruction, preventing regression of left ventricular hypertrophy. Del Rizzo et al60 showed a survival advantage for stentless valves over stented valves, with approximately a 5-fold greater probability of death at 5 years in patients younger than 60 years of age who received stented valves.


?? CHOOSING A BIOPROSTHESIS
 Top
 Previous
 Next
 References
?
The comparative information concerning performance specifications of the various valves is confusing. The body of literature on valve performance and outcome statistics is enormous. It is nearly impossible for an individual surgeon to know enough of these data to make informed choices. A few constants are of some value in interpreting performance characteristics of the various cardiac valve replacement devices. The manufacturer's label size (mm) expresses only an approximate size (diameter) of the prosthesis. For a stent-mounted bioprosthesis the label size correlates with the outside diameter of the stent, not the real outer diameter including the sewing ring. Stentless valves are measured by the actual diameter at the outside of the bioprosthesis, and that is the label size. The label size is always larger than the primary orifice or inside diameter of the device. The primary orifice is often referred to as the internal orifice area or the measured geometric orifice in square centimeters. The primary orifice is difficult, if not impossible, to measure in any bioprosthetic valve. The internal orifice area is always larger than the in vitro orifice area, which is measured by testing the valve in the laboratory in a pulse duplicator. The in vitro orifice area is always larger than the area measured in vivo by Doppler ultrasound after the valve is implanted. The orifice area measured either in vitro or in vivo is also called the effective orifice area (EOA), expressed in square centimeters, and may be "indexed" to body size by dividing by the body surface area (indexed EOA = EOA/BSA). It is noted, however, that body surface area is calculated from both height and weight, so obesity may distort this figure.

Pibarot and Dumesnil61 showed that when valve size and body size are used to calculate an indexed effective valve area, there is a strong relationship between small (19-mm or 21-mm) mechanical or stented bioprosthetic valve size and pressure gradient over the valve during rest and exercise. Del Rizzo et al60 showed that indexed effective orifice area smaller than 0.8 cm2/m2 had a major effect on the extent of left ventricular mass regression after aortic valve replacement with stentless bioprostheses. Dumesnil and Yoganathan have shown that the indexed effective orifice area (cm2/m2) predicts the performance of prosthetic valves during exercise.62 Indexed effective orifice area larger than 0.85 will keep the pressure gradient from rising during exercise on the steep part of performance curves. Indexed effective orifice areas smaller than 0.85 are considered to represent patient-prosthesis mismatch because of the rapid rise in mean pressure gradient observed during exercise.

Stented bioprostheses tend to be on the ascending portion of performance curves more frequently than stentless bioprostheses, homografts, or autografts. The choice of the size of bioprosthesis that can be inserted in the aortic root is actually determined by the size of the aortic root. Inserting an oversized bioprosthesis is of no advantage because stentless bioprostheses may be distorted and therefore obstructive. A stented bioprosthesis that is too large will erode the aortic root tissues, creating immediate problems in adjacent structures or later problems should change of the valve be required. Stented bioprostheses in current use have contoured sewing rings designed to facilitate implantation in a supra-annular position, thereby allowing insertion of a larger device owing to the increased space above the valve annulus provided by the sinus of Valsalva. Stentless bioprostheses must be inserted in an intra-annular position. This may allow devices of similar internal orifice to be implanted and may account for some studies that show equivalent hemodynamic performance of these devices.

Stented xenografts are easy to implant in standard aortic valve replacement procedures and give reproducible results. As noted earlier, however, it is difficult to use a stented heterograft in the small aortic root and it is subject to structural deterioration over time. Homografts are difficult to implant and are in short supply, being dependent on the donor pool. The homograft, however, offers superior hemodynamics and is ideally suited for reconstruction of the small aortic root or for extensive root destruction from prior operation or due to endocarditis. Stentless xenografts, although more difficult to implant than a traditional stented valve, are easier to secure than a homograft due to the stiffness imparted by the fixation technique and also from the cloth covering which is found on some of the valves. As with any valve prosthesis, meticulous technique is required, but the stentless xenografts are more flexible than the stented variety and can therefore be implanted into a smaller aortic root without sacrificing effective valve orifice area.13

Several authors have compared hemodynamics and outcomes between stented and stentless xenografts.6365 Although these studies were retrospective in nature and were not randomized clinical trials, stentless valves have lower rest and exercise gradients than stented valves. In addition, patients receiving stentless valves had lower hospital mortality, fewer reoperations, and lower valve-related mortality than patients receiving stented valves. Long-term survival benefits from stentless valves compared to stented valves have not been reported in a prospective, randomized fashion. There has been one prospective randomized study published to date comparing stentless bioprostheses with stented valves for aortic valve replacement. Cohen et al66 randomized 99 total patients to receive either a stented pericardial valve or a stentless Toronto SPV valve. No difference was shown between the two valves for survival, regression of left ventricular mass, or decrease in transvalvular gradient over the 12-month study period.

Others6770 have compared similar outcomes between stentless xenografts and homografts. Survival, freedom from valve-related complications, and left ventricular remodeling were similar between the two types of valves, although the stentless xenografts had slightly higher gradients. Two of the studies showed a trend toward a higher incidence of aortic valve insufficiency in the Toronto SPV valves. One study71 compared the Toronto SPV, the Biocor PSB, and the Cryolife-O'Brien valves, reporting that the first two were essentially equivalent, while the Cryolife-O'Brien valve had a higher incidence of reoperation and valve deterioration.


?? CONCLUSION
 Top
 References
?
In summary, stentless xenografts are being more widely used for replacement and reconstruction of aortic valve and root pathology. Some of the stentless bioprostheses can be tailored by the surgeon to repair part or all of the aortic root, and all of the stentless valves are suitable for patients with a small aortic root. Although the implantation technique is more difficult than standard aortic valve replacement with a stented xenograft, it is not as demanding as homograft implantation. Stentless xenografts in patients have resulted in improved functional class and exercise performance presumably due to excellent hemodynamic performance, and reoperation for valve-related causes is unusual. There is high freedom from valve-related complications such as thromboembolism and endocarditis. Stentless bioprostheses do not require anticoagulation. Mechanical stress to the leaflets is theoretically less due to the absence of the stent, although long-term data are not yet available to support this contention. Newer anticalcification treatments developed for the stentless xenografts may reduce or prevent valve and/or aortic calcification over time. Survival, functional classification, and freedom from valve deterioration are excellent at mid-term follow-up (510 years) for all types of stentless bioprostheses. Long-term follow-up will ultimately determine the role of these valves. At present, however, stentless bioprostheses should be carefully considered whenever aortic valve replacement is required and may be the device of choice in patients older than 70 years having a 19- to 21-mm aortic annulus.


?? REFERENCES
 Top
?
  1. Binet JP, Duran CG, Carpentier A, et al: Heterologous aortic valve transplantation. Lancet 1965; 2:1275.[Medline]
  2. O'Brien MF: Heterograft aortic valves for human use. J Thorac Cardiovasc Surg 1967; 53:392.[Medline]
  3. David TE, Pollick C, Bos J: Aortic valve replacement with stentless porcine aortic bioprosthesis. J Thorac Cardiovasc Surg 1990; 99:113.[Abstract]
  4. Walther T, Falk V, Autschbach R, et al: Comparison of different anticalcification treatments for stentless bioprostheses. Ann Thorac Surg 1998; 66:S249.
  5. Girardot MN, Torrianni MW, Girardot JM: Effect of AOA on glutaraldehyde-fixed bioprosthetic heart valve cusps and walls: binding and calcification studies. Int J Artif Organs 1994; 17:76.[Medline]
  6. Chen W, Schoen FJ, Levy RJ: Mechanism of efficacy of 2-amino oleic acid for inhibition of calcification of glutaraldehyde pretreated porcine bioprosthestic heart valves. Circulation 1994; 90:323.[Medline]
  7. Mayne ASD, Christie GW, Smaille BH, et al: An assessment of the mechanical properties of leaflets from four second generation porcine bioprostheses using biaxial testing techniques. J Thorac Cardiovasc Surg 1989; 98:170.[Abstract]
  8. Carpentier A, Nashef A, Carpentier S, et al: Techniques for prevention of calcification of valvular bioprostheses. Circulation 1984; 70(suppl I):165.[Medline]
  9. Herijgers P, Ozaki S, Verbeken E, et al: The No-React anticalcification treatment: a comparison of Biocor No-React II and Toronto SPV stentless bioprostheses implanted in sheep. Semin Thorac Cardiovasc Surg 1999; 11:171.[Medline]
  10. Abolhoda A, Yu S, Oyarzun JR, et al: No-React detoxification process: a superior anticalcification method for bioprostheses. Ann Thorac Surg 1996; 62:1724.[Abstract/Free?Full?Text]
  11. Westaby S, Jin XY, Vaccari G, Katsumota T: The Sorin stentless pericardial valve: implant techniques and hemodynamic profile. Semin Thorac Cardiovasc Surg 1999; 11:62.[Medline]
  12. David TE, Feindel CM, Scully HE, et al: Aortic valve replacement with stentless porcine aortic valves: a ten-year study. J Heart Valve Dis 1998; 7:250.[Medline]
  13. Doty JR, Flores JH, Millar RC, Doty DB: Aortic valve replacement with Medtronic Freestyle bioprosthesis: operative technique and results. J Card Surg 1998; 13:208.[Medline]
  14. Krause AH Jr: Technique for complete subcoronary implantation of the Medtronic Freestyle porcine bioprosthesis. Ann Thorac Surg 1997; 64:1495.[Abstract/Free?Full?Text]
  15. Pepper JR: The stentless porcine valve. J Card Surg 1998; 13:352.[Medline]
  16. Sintek CF, Fletcher AD, Khonsari S: Small aortic root in the elderly: use of stentless bioprosthesis. J Heart Valve Dis 1996; 5(suppl III):S308.
  17. Westaby S, Amarasena N, Ormerod O, et al: Aortic valve replacement with the Freestyle stentless xenograft. Ann Thorac Surg 1995; 60:S422.
  18. Flynn M, Iaccovoni A, Pathi V, et al: The aortic Elan stentless aortic valve: excellent hemodynamics and ease of implantation. Semin Thorac Cardiovasc Surg 2001; 13(4 suppl):48.[Medline]
  19. Huysmans H: Implanting the Freestyle bioprosthesis: root-inclusion technique: the Freestyle aortic root bioprosthesis implant technique monograph. Minneapolis, MN, Medtronic, Inc., 1997.
  20. Kon ND, Westaby S, Amarasena N, et al: Comparison of implantation techniques using Freestyle stentless porcine aortic valve. Ann Thorac Surg 1995; 59:857.[Abstract/Free?Full?Text]
  21. Doty DB, Cafferty A, Cartier P, et al: Aortic valve replacement with Medtronic Freestyle bioprosthesis: 5-year results. Semin Thorac Cardiovasc Surg 1999; 2(suppl 1):35.
  22. Doty DB, Cafferty A, Cartier P, et al: Aortic valve replacement with Medtronic Freestyle bioprosthesis: seven year results. Presentation at Medtronic Freestyle Valve Symposium, Salt Lake City, UT, May 18, 2001.
  23. Doty DB, Cafferty A, Kon ND, et al: Medtronic Freestyle aortic root bioprosthesis: implant techniques. J Card Surg 1998; 13:369.[Medline]
  24. Dagenais F, Cartier P, Dumesnil JG, et al: A single center experience with the Freestyle bioprosthesis: midterm results at the Quebec Heart Institute. Semin Thorac Cardiovasc Surg 2001; 13(4 suppl):156.[Medline]
  25. Kappetein AP, Braun J, Baur LHB, et al: Outcome and follow-up of aortic valve replacement with the Freestyle stentless bioprosthesis. Ann Thorac Surg 2001; 71:691.
  26. Cartier PC, Dumesnil JG, Metras J, et al: Clinical and hemodynamic performance of the Freestyle aortic root bioprosthesis. Ann Thorac Surg 1999; 67:345.[Abstract/Free?Full?Text]
  27. Kon ND, Cordell AR, Adair SM, et al: Aortic root replacement with the Freestyle stentless porcine aortic root bioprosthesis. Ann Thorac Surg 1999; 67:1609.[Abstract/Free?Full?Text]
  28. Westaby S, Jin XY, Katsumata T, et al: Valve replacement with a stentless bioprosthesis: versatility of the porcine aortic root. J Thorac Cardiovasc Surg 1998; 116:477.[Abstract/Free?Full?Text]
  29. Goldman BS, David TE, Wood JR, et al: Clinical outcomes after aortic valve replacement with the Toronto stentless porcine valve. Ann Thorac Surg 2001; 71:S302.[Abstract/Free?Full?Text]
  30. Sintek CF, Pfeffer TA, Kochamba GS, et al: Freestyle valve experience: technical considerations and mid-term results. J Card Surg 1998; 13:360.[Medline]
  31. Goldman B, Christakis G, David T, et al: Will stentless valves be durable? The Toronto Valve (TSPV) at 5 to 6 years. Semin Thorac Cardiovasc Surg 1999; 11:42.[Medline]
  32. Shargall Y, Goldman B, Christakis G, David T: Analysis of explants and causes of mortality during long-term follow-up of the Toronto stentless porcine valve. Semin Thorac Cardiovasc Surg 2001; 13(4 suppl):106.
  33. Williams RJ, McLean AD, Pathi VL, et al: Six-year follow-up of the Toronto stentless porcine valve. Semin Thorac Cardiovasc Surg 2001; 13(4 suppl):168.
  34. David TE, Feindel CM, Bos J, et al: Aortic valve replacement with a stentless porcine aortic valve. J Thorac Cardiovasc Surg 1994; 108:1030.[Abstract/Free?Full?Text]
  35. Gelsomino S, Frassani R, DaCol P, et al: The Cryolife-O'Brien stentless porcine aortic bioprosthesis: 5-year follow-up. Ann Thorac Surg 2001; 71:86.[Abstract/Free?Full?Text]
  36. Hvass U, Palatianos GM, Frassani R, et al: Multicenter study of stentless valve replacement in the small aortic root. J Thorac Cardiovasc Surg 1999; 117:267.[Abstract/Free?Full?Text]
  37. O'Brien MF, Gardner MAH, Garlick RB, et al: The Cryolife-O'Brien stentless aortic porcine xenograft valve. J Card Surg 1998; 13:376.[Medline]
  38. Jin XY, Ratnatunga C, Pillai R: Performance of Edwards prima stentless aortic valve over eight years. Semin Thorac Cardiovasc Surg 2001; 13(4 suppl):163.
  39. Bortolotti U, Scioti G, Milano A, et al: The Edwards Prima stentless valve: hemodynamic performance at one year. Ann Thorac Surg 1999; 68:2147.[Abstract/Free?Full?Text]
  40. Jin XY, Dhital K, Bhattacharya K, et al: Fifth-year hemodynamic performance of the Prima stentless aortic valve. Ann Thorac Surg 1998; 66:805.[Abstract/Free?Full?Text]
  41. Dossche K, Vanermen H: Experience with the Edwards Prima stentless aortic bioprosthesis: a 2-year review. J Heart Valve Dis 1995; 4:S85.
  42. Vrandecic M, Fantini FA, Filho BG, et al: Long-term results with the Biocor-SJM stentless porcine aortic bioprosthesis. J Heart Valve Dis 2002; 11:47.[Medline]
  43. Bertolini P, Luciani GB, Vecchi B, et al: Aortic valve replacement with the Biocor PSB stentless xenograft. Ann Thorac Surg 1998; 66:425.[Abstract/Free?Full?Text]
  44. Del Rizzo DF, Abdoh A: Clinical and hemodynamic comparison of the Medtronic Freestyle and Toronto SPV stentless valves. J Card Surg 1998; 13:398.[Medline]
  45. Legare JF, Wood JW, Koilpillai C, et al: St. Jude SPV versus Medtronic Freestyle: a single institution comparison of two stentless aortic valves. J Card Surg 1998; 13:392.[Medline]
  46. Bach DS, Goldman B, Verrier E, et al: Eight-year hemodynamic follow-up after aortic valve replacement with the Toronto SPV stentless aortic valve. Semin Thorac Cardiovasc Surg 2001; 13(suppl 1):173.[Medline]
  47. Barratt-Boyes BG, Christie GW: What is the best bioprosthetic operation for the small aortic root? Allograft, autograft, porcine or pericardial? Stented or unstented? J Card Surg 1994; 9:158.[Medline]
  48. Sintek CF, Fletcher AD, Khonsari S: Stentless porcine aortic root: valve of choice for the elderly patient with small aortic root. J Thorac Cardiovasc Surg 1995; 109:871.[Abstract]
  49. Westaby S, Amarasena N, Long V, et al: Time-related hemodynamic changes after aortic replacement with the Freestyle stentless xenograft. Ann Thorac Surg 1995; 60:1633.[Abstract/Free?Full?Text]
  50. Del Rizzo DF, Goldman BS, Christakis GT, et al: Hemodynamic benefits of the Toronto stentless valve. J Thorac Cardiovasc Surg 1996; 112:1431.[Abstract/Free?Full?Text]
  51. Fries R, Wendler O, Schieffer H, et al: Comparative rest and exercise hemodynamics of 23-mm stentless versus 23-mm stented aortic bioprostheses. Ann Thorac Surg 2000; 69:817.[Abstract/Free?Full?Text]
  52. Nagy ZL, Fisher J, Walker PG, et al: The effect of sizing on the hydrodynamic parameters of the Medtronic Freestyle valve in vitro. Ann Thorac Surg 2000; 69:1408.[Abstract/Free?Full?Text]
  53. De Paulis R, Sommariva L, Colagrande L, et al: Regression of left ventricular hypertrophy after aortic valve replacement for aortic stenosis with different valve substitutes. J Thorac Cardiovasc Surg 1998; 116:590.[Abstract/Free?Full?Text]
  54. Walther T, Falk V, Langebartels G, et al: Regression of left ventricular hypertrophy after stentless versus conventional aortic valve replacement. Semin Thorac Cardiovasc Surg 1999; 11:18.[Medline]
  55. Maselli D, Pizio R, Bruno LP, et al: Left ventricular mass reduction after aortic valve replacement: homografts, stentless and stented valves. Ann Thorac Surg 1999; 67:966.[Abstract/Free?Full?Text]
  56. Jin XY, Zhang ZM, Gibson DG, et al: Effects of valve substitute on changes in left ventricular function and hypertrophy after aortic valve replacement. Ann Thorac Surg 1996; 62:683.[Abstract/Free?Full?Text]
  57. Bach DS: Echocardiographic assessment of stentless aortic bioprosthetic valves. J Am Soc Echocardiogr 2000; 13:941.[Medline]
  58. Bauer LHB, Jin XY, Houdas Y, et al: Echocardiographic parameters of the Freestyle stentless bioprosthesis in aortic position: the European experience. J Am Soc Echocardiogr 1999; 12:729.[Medline]
  59. Westaby S, Horton M, Jin XY, et al: Survival advantage of stentless aortic bioprostheses. Ann Thorac Surg 2000; 70:785.[Abstract/Free?Full?Text]
  60. Del Rizzo DF, Abdoh A, Cartier P, et al: Factors affecting left ventricular mass regression after aortic valve replacement with stentless valves. Semin Thorac Cardiovasc Surg 1999; 8:114.
  61. Pibarot P, Dumesnil JG, Lemieux M, et al: Impact of prosthesis-patient mismatch on hemodynamic and symptomatic status, morbidity and mortality after aortic valve replacement with a bioprosthetic heart valve. J Heart Valve Dis 1998; 7:211.[Medline]
  62. Dumesnil JG, Yoganathan AP: Valve prosthesis hemodynamics and the problem of high transprosthetic pressure gradients. Eur J Cardiothorac Surg 1992; 6(suppl I):S34.
  63. David TE, Psuchmann R, Ivanov J, et al: Aortic valve replacement with stentless and stented porcine valves: a case-match study. J Thorac Cardiovasc Surg 1998; 116:236.[Abstract/Free?Full?Text]
  64. Rao V, Christakis GT, Sever J, et al: A novel comparison of stentless versus stented valves in the small aortic root. J Thorac Cardiovasc Surg 1999; 117:431.[Abstract/Free?Full?Text]
  65. Vrandecic M, Fantini FA, Filho BG, et al: Retrospective clinical analysis of stented vs. stentless porcine aortic bioprostheses. Eur J Cardiothorac Surg 2000; 18:46.[Abstract/Free?Full?Text]
  66. Cohen G, Christakis GT, Joyner CD, et al: Are stentless valves superior to stented valves? A prospective randomized trial. Ann Thorac Surg 2002; 73:676.
  67. Gross C, Harringer W, Beran H, et al: Aortic valve replacement: is the stentless xenograft an alternative to the homograft? Midterm results. Ann Thorac Surg 1999; 68:919.[Abstract/Free?Full?Text]
  68. Kon ND, Cordell AR, Adair SM, et al: Comparison of results using "Freestyle" stentless porcine aortic root bioprosthesis with cryopreserved aortic allograft. Semin Thorac Cardiovasc Surg 1999; 11:69.[Medline]
  69. Rajappan K, Melina G, Bellenger NG, et al: Evaluation of left ventricular function and mass after Medtronic Freestyle versus homograft aortic root replacement using cardiovascular magnetic resonance. J Heart Valve Dis 2002; 11:60.[Medline]
  70. Riley RD, Hammon JW Jr, Adair SM, et al: Stentless aortic valve replacement with Freestyle or Toronto SPV: an early comparison. Ann Thoracic Surg 2000; 70:48.[Abstract/Free?Full?Text]
  71. Luciani GB, Bertolini P, Vecchi B, et al: Midterm results after aortic valve replacement with freehand stentless xenografts: a comparison of three prostheses. J Thorac Cardiovasc Surg 1998; 115:1287.[Abstract/Free?Full?Text]




This Article
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this book
Right arrow Author home page(s):
Donald B. Doty
John R. Doty
Google Scholar
Right arrow Articles by Doty, D. B.
Right arrow Articles by Doty, J. R.
Right arrow Articles citing this Article
Right arrow Search for Related Content
PubMed
Right arrow Articles by Doty, D. B.
Right arrow Articles by Doty, J. R.
Related Collections
Right arrow Valve disease