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Ann Thorac Surg 2001;71:92-99
© 2001 The Society of Thoracic Surgeons
a Cardiothoracic Research Laboratory, Carlyle Fraser Heart Center, Crawford Long Hospital, Emory University School of Medicine, Atlanta, Georgia, USA
Accepted for publication February 28, 2000.
Address reprint requests to Dr Brown, Division of Cardiothoracic Surgery, Crawford Long Hospital, 550 Peachtree St, Suite 7700, Atlanta, GA 30365
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Abstract |
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 TopFootnotes Abstract IntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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-amino oleic acid (AOA), and a proven stent design. We tested the hypothesis that AOA treatment of Mosaic valves improves hemodynamics, antimineralization properties, and survival in a chronic ovine model. Methods. Mitral valves were implanted in juvenile sheep with Mosaic valves with AOA treatment (n = 8) or without AOA treatment (non-AOA, n = 8), or Hancock I (HAN, n = 4) tissue valves, and explanted at 20 postoperative weeks.
Results. Survival was equivalent in AOA and non-AOA (140 ± 0.4 and 129 ± 30 days), but was significantly less in HAN (82 ± 35). Leaflet calcium (µgCa/mg tissue) was less in AOA (9.6 ± 13.9; p < 0.05 versus non-AOA and HAN) than non-AOA (96.3 ± 63.8) and HAN (130.8 ± 43.2). Explant valve orifice area (cm2) was significantly preserved in the AOA group compared with the non-AOA group (1.5 ± 0.7 vs 0.8 ± 0.3; p < 0.05 versus non-AOA and HAN).
Conclusions. We conclude that AOA treatment of Mosaic valves reduces leaflet calcification and valve gradient in juvenile sheep, and that the Mosaic design and fixation features may offer survival advantages that must be confirmed in extended trials.
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Introduction |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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-amino oleic acid (AOA) antimineralization treatment and root pressure fixation from the Freestyle valve, and the stent design from the Hancock II valve [2, 8–13]. This combination of features is proposed to enhance the durability and inhibit the calcification of the porcine bioprosthesis. We evaluated the hemodynamic, histologic, and antimineralization properties of the Mosaic valve in a juvenile sheep model acknowledged for accelerated calcification of tissue valves. |
Material and methods |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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The juvenile sheep (Ovis aries) model is well recognized for accelerated calcification causing significant dysfunction of the replaced valve within 4 to 6 months [14–16]. These changes are morphologically similar to those found in similar valves implanted in human beings for considerably longer periods of time and thus provides an acceptable model for the evaluation of bioprosthetic heart valves. Juvenile sheep accepted into the study were 3 to 5 months of age, approximately 30 to 40 kg in weight, and either female or neutered male.
Test material
The test material consisted of Mosaic valves treated with AOA (group I, n = 8), Mosaic valves without AOA treatment (group II, n = 8), and Hancock Type I valves (group III, n = 4). All valves were 25 mm annular diameter in size, were of clinical quality, and had undergone single-pass flow testing (SPFT) before shipment for implantation. The order of implantation of valves was determined by random selection.
Hematologic studies
Hematologic and serum chemistry studies were obtained 5 to 10 days preoperatively, 7 to 10 days postoperatively, 10 and 20 weeks postoperatively, or immediately before elective termination. Studies performed included complete blood count, serum chemistry profile, indices of hemolysis, and coagulation parameters.
Surgical method
After an overnight fast, atropine (0.2 mg/kg subcutaneously) and xylazine (0.1 mg/kg intramuscularly) were administered as premedication. Preoperatively, cefazolin (1 g intravenously [IV]) was administered, thiopental 2.2 mg/kg followed by lidocaine 2.2 mg/kg were given for induction, and the animal was endotracheally intubated and mechanical ventilation was instituted. A pulmonary artery catheter was then passed through the right jugular vein, and a percutaneous catheter was placed into the right femoral artery or internal thoracic artery for arterial blood pressure monitoring. The animal was then placed in a right lateral decubitus position, administered pancuronium bromide (0.01 mg/kg IV), and a left thoracotomy was performed. Venous return was obtained by way of retrograde cannulation of the right ventricle through the pulmonary artery, and the descending aorta was cannulated for arterial inflow. Bypass was initiated, the animal cooled to 28°C, and antegrade, oxygenated, cold crystalloid cardioplegia was delivered for myocardial protection. A pledgetted 2–0 Prolene (Ethicon, Inc, Somerville, NJ) suture was passed around the left main coronary artery and carefully occluded with a Rumel tourniquet after delivery of cardioplegia solution to prevent coronary air emboli.
After cardioplegic arrest, a left atriotomy was performed and the anterior leaflet of the native mitral valve was excised, preserving the mural leaflet and its chordal attachments. The rinsed bioprosthetic valve was implanted using interrupted, pledgetted, atrially based 2-0 or 3-0 Ti-Cron (Davis and Geck, Danbury, CT) braided polyester suture. Handling characteristics at the time of implantation were documented.
Once the animal had achieved a stable blood pressure and heart rate after weaning from bypass, hemodynamic study of the valve was performed. Cardiac output was measured by thermodilution using the pulmonary artery catheter. Sterile Mikro-tip (Millar, Houston, TX) pressure transducer catheters were placed into the left atrium and left ventricle through the atriotomy incision (left ventricular catheter across the mitral valve). Valve gradients were documented and orifice areas derived from the modified Gorlin formula for the mitral valve [17]. Data were acquired using a Hewlett-Packard (model 7758B, Andover, MD) physiologic monitoring system, and stored and analyzed utilizing the CARLA data acquisition and analysis program developed at Emory University (J. M. Bradford, PhD). After data had been acquired, the catheters and pressure transducers were removed and the animal was weaned from the ventilator and extubated. Nalbuphine (1 mg/kg) IV was administered for postoperative analgesia and given penicillin benzathine and procaine penicillin G (1 million units IM daily) for a minimum of 3 days postoperatively. No long-term medications were used during the study, including anticoagulants or antiplatelet agents.
Elective termination studies
A total of 7 animals died during the study. Four sheep died intraoperatively or within 48 hours of surgery and these were considered surgical deaths and excluded from the study. Of the 20 sheep that survived the initial postoperative period and were consequently included in the study, 3 animals (group II, n = 1; group III, n = 2) died before completion of the postoperative study period, but were included in the mortality statistics and underwent full autopsy within 24 hours post mortem. Elective studies were performed on or close to the specified date of 20 weeks (140 days) after implantation. Loss of the animal before completion of 20 weeks was deemed imminent in 3 cases (group II, n = 1; group III n = 2) due to cardiopulmonary complications, and the animal underwent early explantation analysis as per protocol guidelines.
Anesthesia was induced using premedication with xylazine (0.05 mg/kg) and induction with diazepam (0.275 mg/kg) and ketamine (2.75 mg/kg). The animal was endotracheally intubated and ventilated. Right anterior and left anterior oblique ventriculograms were acquired using a 5 F catheter (Cordis, Miami, FL) inserted into the right femoral artery and advanced to the left ventricle. After completion of the ventriculograms, the heart was exposed through a median sternotomy. A pulmonary artery catheter was introduced through the anterior superior vena cava and advanced to the level of the pulmonary artery. Mikro-tip catheter pressure transducers were inserted into the left ventricle through a stab incision in the ventricular apex and into the left atrium through the right superior pulmonary vein. Cardiac output was determined by thermodilution using the pulmonary artery catheter. The Mikro-tip catheters were used to simultaneously record the left ventricular and left atrial pressures, determine the gradient, and calculate the valve area. After completion of the hemodynamic studies, the animal was heparinized and euthanized with an intravenous injection of potassium chloride (2 mg/kg). The heart was excised under aseptic conditions and a detailed postmortem examination performed including the heart and other internal organs. Histopathologic examination of representative tissue sections and any lesions of the major target organs (myocardium, lungs, liver, spleen, kidneys, and brain) was performed and documented.
Explanted valve analysis
After excision of the bioprosthetic valve and surrounding myocardium, the valve immediately underwent detailed gross inspection. Specific pathologic features that were assessed included leaflet pliability, leaflet insertion dehiscence, tissue overgrowth, thrombi, cuspal hematomas, calcifications, vegetations, fenestration or tears, stretching, abrasion, suture interactions, and structural relationships. Macrophotographs of the valve block were then taken and the valve was radiographed using mammographic film. Using these radiographs, the degree of cuspal calcification was assessed, excluding the commissures and valve wall [11].
The valve cusps were then dissected from the stent and longitudinal sections from each leaflet were obtained. Sections 2 to 6 µm thick were evaluated histologically using sections stained with hematoxylin and eosin, Movat’s pentachrome stain for collagen, elastin and mucopolysaccharide, and von Kossa’s stain for calcium phosphates. The remainder of the leaflets were then rinsed with distilled water, frozen, lyophilized, weighed, and acid hydrolyzed with 1 mL 6 N HCl at 80° C. The samples were then dried and reconstituted with 1 mL 0.01 N HCl. Quantitative calcium levels were then obtained by atomic absorption spectrometry.
Statistical analysis
Standard descriptive statistics including means, standard deviations, medians, and ranges were used to characterize the three samples from the AOA-treated Mosaic valve group, the untreated Mosaic valve group, and the Hancock I control group. Data are presented as mean ± standard deviation. All statistical analyses were performed using SAS (SAS Institute, Cary, NC) software. For variables that were continuous measures, the comparisons between the three groups were made using a one-way analysis of variance (ANOVA) for normally distributed data or a Kruskal-Wallis test for variables that did not appear normally distributed, such as the degree of mineralization. Posthoc pairwise comparisons to locate the source of differences were carried out using Tukey’s studentized range tests. For features that were measured both at implant and at follow-up, a repeated measures ANOVA was carried out to assess time, group, and time by group effects. Tukey’s post hoc comparisons were used to evaluate where differences existed when significant main effects were observed. For features that were categorical, the association with group was made using Fisher’s exact test due to small sample size. The p values are unadjusted for the number of comparisons but conclusions regarding associations are based on adjustment for this multiplicity. Differences were considered significant if p is less than 0.05.
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Results |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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SPFT valve orifice area (cm2), calculated upon construction of the valve (before implantation) at Medtronic Heart Valve, Inc, was greater in group I versus group III (2.0 ± 0.1 versus 1.8 ± 0.1, p = 0.04), and similar to group II (2.0 ± 0.1, Fig 1A). Valve packaging was standard and easy to handle across the three groups. Valve identification was clear and easily appreciated. The valve annulus sizer was simple to use and valve holder performed adequately. The sewing ring was appropriately sized and easily penetrated by the suture needle, with acceptable suture drag in all groups.
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As only 2 animals from group III were available for explant hemodynamic study, this group (n = 2) was eliminated from statistical analysis of hemodynamic performance. At explantation, the pressure gradient (mm Hg) was similar across the AOA-treated Mosaic valves (group I, 6.5 ± 3.9) and the group II valves (13.4 ± 6.7; p = 0.19). Cardiac output (L/min) was similar among the two groups: 8.1 ± 2.2 for group I and 6.3 ± 2.1 for group II (p = 0.92). Explant valve area (cm2), however, was significantly greater for AOA-treated Mosaic valves (1.5 ± 0.7) compared with group II valves (0.8 ± 0.3; p = 0.04; Fig 1B).
On gross visual inspection of the explanted valves, all valve leaflets in group II and 3 valve leaflets in group III were found to be stiff and nonpliable when saline was gently poured on the inflow surface. Host tissue overgrowth (pannus) was evident extending out onto the sewing ring and, in several cases, onto the proximal leaflets themselves, irrespective of the valve group (Fig 2). Thrombotic deposits were noted on the majority of group I and group II valves (1 mm to 1 cm), but only in 1 of the group III valves. These accumulations were typically located along the inflow aspect of the commissures but did not appear to limit leaflet mobility. Extensive gross mineralization was noted on the leaflets in all group II and group III valves but only minimally at the commissure-wall junction of 1 of the group I valves. In several cases, these calcifications were associated with small tears/abrasions visible on the cusps. No valve displayed evidence of leaflet insertion dehiscence, fenestration, stretching, or suture interactions.
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On histopathologic analysis, valve calcification was also considerably greater in the group II and group III valves as compared with the group I valves. Valvular thrombus formation, defined as the deposition of fibrinous material on the surface of the leaflets, was evident in the majority of the group I and group II valves (Fig 6). The group III valves, all removed before the completion of 40 weeks, revealed less visible accumulation of thrombotic material, although a small number were still present. Trilaminar structure disruption or compromise was prominent in both groups of Mosaic valves, with or without AOA treatment, as compared with the group III valves.
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At postmortem examination, all animals demonstrated evidence of alveolar smooth muscle hyperplasia due to exertional respirations, secondary to dense adhesions formed between the left pleura and left lateral chest wall at the site of the previous thoracotomy. Also present in the majority of animals was subendocardial fibrosis around the cardiac annulus, secondary to the implantation of the bioprosthetic valve. On autopsy, the early deaths in group III (n = 2) and group II (n = 1), and the 2 additional early explants in group III were found to have evidence of congestive heart failure: hydrothorax, pulmonary edema, and hepatic centrilobular necrosis, consistent with their clinical symptoms. These deaths were felt to be due to cardiopulmonary deterioration, secondary to severe calcific mitral stenosis.
One additional sheep in group II was prematurely explanted 134 days postimplantation. At autopsy, it was found to have similar pulmonary parenchymal changes and endocardial fibrosis, but was also noted to have a mild, diffuse, suppurative, periportal hepatitis. This hepatic pattern was felt most likely to be due to subclinical bacteremia. The animal had an earlier episode of fever of unknown origin, beginning day 124 postoperation, which resolved with 1 week of antibiotic treatment.
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Comment |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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Leaflet calcification is considered the principal element in the diminished durability of tissue valve replacements [1, 4]. As such, a variety of bioengineering innovations have been evaluated as a means of impeding tissue valve calcification. One such recent effort utilizes 2-AOA treatment of gluteraldehyde-preserved porcine aortic valves. In a previous study [11] of AOA-treated mitral valves in a juvenile sheep model, it was thought that the hydrophobic lipid moieties of the covalently bound AOA molecules prevent calcium implantation in the tissue stroma. There was a significant reduction in mean quantitative leaflet calcium content (µg/mg) of AOA-treated versus a standard 25-mm porcine bioprosthesis: 7.7 ± 5.8 versus 129 ± 21 (p < 0.001) [11]. However, there was worrisome structural disruption associated with AOA fixation. As the AOA treatment was refined to minimize structural deterioration associated with fixation, interest in this novel technique grew [13]. The Mosaic bioprosthesis was designed incorporating elements of the Intact, Hancock II, and Freestyle valves.
In the current study in a chronic juvenile sheep model, tissue calcification was significantly diminished in the AOA-treated Mosaic valves as compared with the non-AOA and standard Hancock I valves, as per radiographic valve calcification score and quantitation of cuspal calcium and phosphate levels. Unlike the earlier AOA studies, we also found less annular wall calcium and phosphate content in the Mosaic valves, perhaps reflecting an increased penetration of AOA into the wall of the valve as efficient as that for the leaflet themselves [10]. The enhanced antimineralization characteristics were associated with the improved explant hemodynamic characteristics of the AOA-treated Mosaic valves, including increased valve orifice area.
Most significantly, however, the diminished calcification properties of the AOA-treated Mosaic valves correlated with a significant survival advantage as compared with standard clinically utilized Hancock I valves. This enhanced survival had not been previously reported. The earlier deaths in the Hancock I group may explain why less extensive trilaminar disruption was seen in these valves, as they were exposed to fewer mechanical open-close cycles. Consequently one may infer they were exposed to less fatigue-related disruption. The longer duration of implantation and increased mobility may also account for the presence of valvular thrombi on the cusps of the majority of the Mosaic valves, both with and without AOA. These excrescences were found predominantly along the inflow surface of the valve commissures. Similar abnormalities were first reported in the initial communications from the National Institutes of Health studies of bioprosthetic valves implanted in the juvenile sheep model. Jones and coworkers [15] reported their findings of the first 99 valve implants including porcine aortic valves, bovine pericardial valves, and a few glycerol-treated human dura mater valves. They reported that histopathologic abnormalities including "microthrombi, fibrous sheathing of the leaflet tissue, intracuspal hematomas..." were identified in all of the 76 valves in sheep surviving at least 1 month. Although the deposits observed in the valves in our study would appear to be more extensive than those described by Jones and associates, they did not appear to impede valve function and did not result in diminished animal survival or gross pathologic findings on postmortem examination. The significance of these abnormalities however, remains to be fully elucidated and warrants continued investigation.
In conclusion, the AOA-treated Mosaic valve was demonstrated to have profoundly reduced wall and leaflet calcification in this juvenile sheep model. Despite the presence of thrombotic accumulations at the valve commissures, the AOA-treated Mosaic valve exhibited improved hemodynamic performance. Perhaps most significantly, sheep implanted with these valve had improved survival compared with currently used Hancock I valves. This novel bioprosthesis may translate clinically into a reduced risk of reoperation, and subsequently a possible increase in patient survival.
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Footnotes |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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TopFootnotesAbstractIntroductionMaterial and methodsResultsCommentAcknowledgmentsReferences |
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