Alpha-amino Oleic Acid Research Articles

Clinical results of the Medtronic Mosaic porcine bioprosthesis up to 13 years

The Mosaic bioprosthesis is a third-generation stented porcine bioprosthesis combining physiologic fixation and alpha-amino oleic acid (AOA) antimineralisation treatment to improve haemodynamic performance and durability. This single-centre study reports the clinical results, including haemodynamic performance, of the Mosaic bioprosthesis after implant in aortic or mitral position. Between February 1994 and October 1999, 255 patients with aortic valve replacement (AVR; mean age: 67 years, range: 23-82 years) and 47 patients with mitral valve replacement (MVR; mean age: 67 years, range: 41-84 years) were enrolled in this prospective non-randomised clinical trial. Follow-up visits were performed 30 days and 6 months after implant and annually thereafter. The cumulative follow-up was 1976.2 patient-years (pt-yrs) after AVR (median: 8.3 years, maximum: 14.0 years) and 336.9 pt-yrs after mitral valve replacement (MVR) (median: 8.2 years, maximum: 13.3 years). After AVR, mean systolic gradient and effective orifice area at 4, 8 and 13 years follow-up were 13.3+/-5.6, 15.5+/-7.7 and 16.0+/-7.2 mmHg and 1.8+/-0.5, 1.8+/-0.5 and 1.7+/-0.4 cm(2). After MVR, respective data were 4.7+/-2.1, 4.3+/-1.2 and 5.0 mmHg (only one recording) and 2.2+/-0.7, 2.3+/-0.6 and 1.8 cm(2). Transvalvular regurgitation at 13-year follow-up was mild or less in both the AVR and MVR patients. Thirteen-year survival was 63.1+/-4.5% in the AVR group and 51.2+/-13.6% in the MVR group. Early mortality after AVR and MVR was 1.2% and 0.0%, respectively; late mortality was 3.2%pt-yr(-1) and 3.3%pt-yr(-1), including a valve-related/unexplained mortality of 1.1%pt-yr(-1) and 0.9%pt-yr(-1). Freedom from adverse events in the AVR and MVR group was permanent neurological event: 97.4+/-1.2% and 96.0+/-3.9%; valvular thrombosis: 97.8+/-1.1% and 100%; structural valve deterioration: 84.8+/-7.8% and 93.8+/-6.1%; explant: 73.3+/-7.3% and 89.3+/-6.5%. The Mosaic bioprosthesis demonstrates excellent clinical performance and safety after 13 years of follow-up. Continued follow-up will determine whether this new design will provide increased durability.

Inflammation and infection in nine surgically explanted Medtronic Freestyle® stentless aortic valves

The Medtronic Freestyle valve is fixed in glutaraldehyde at zero pressure on the cusps and treated with alpha-amino oleic acid. This valve reportedly has excellent clinical and hemodynamic results, but little has been reported about its long-term pathology. Nine Freestyle valves explanted between 2003 and 2005 were reviewed to assess the reasons for bioprosthesis failure (six implanted at our institution). All valves were examined in detail, using histochemistry and immunohistochemistry to identify the cellular response. One Freestyle valve, explanted for mitral valve endocarditis on the fifth postoperative day, was excluded from analysis. Average implant duration was 52.8+/-35.5 months. Four valves were explanted for infective endocarditis, three for aortic insufficiency, two for aortic stenosis with cusp calcification seen in five valves, pannus and thrombus in all valves and a chronic inflammatory reaction involving the xenograft arterial wall seen in eight of nine valves. This was associated with significant damage to the porcine aortic wall in seven cases, and cusp myocardial shelf damage in six cases. In this series of valves, we found (1) infective endocarditis; (2) pannus, thrombus, and calcification; and (3) unusual and significant inflammatory reaction and aortic tissue damage, which could by itself lead to aortic incompetence.

Carbodiimide Treatment Dramatically Potentiates the Anticalcific Effect of Alpha-Amino Oleic Acid on Glutaraldehyde-Fixed Aortic Wall Tissue

Background Bifunctional amines were previously found to act as bridging molecules between the terminal ends of incomplete glutaraldehyde (GA) cross-links. The additional cross-links thus formed between ε-NH 2 groups of tissue were seen to significantly inhibit bioprosthetic calcification. In the current study, the potential ability of α-amino oleic acid (AOA) to act as a bridging molecule between ε-NH 2- and COOH-dependent cross-links was hypothesized to similarly augment the anticalcification effect of the AOA molecule. Methods Porcine aortic wall tissue from Medtronic Freestyle valve bioprostheses incorporating the AOA anticalcification process additionally underwent carboxyl-group cross-linking with Jeffamine (poly[propylene glyco]-bis-[aminopropyl ether]) using 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). Tissue was subdermally implanted into 5-week-old Long-Evans rats for 60 days. Standard 0.2% GA-fixed tissue served as a control. To further assess the impact of storage solution on AOA tissue, samples were either stored in GA (0.2%GA) or EDC (25 mmol/L carbodiimide) before implantation. Tissue calcification was assessed by atomic absorption spectroscopy and histochemical staining. Results Aldehyde end-capping with AOA achieved only a modest reduction of calcification in GA-treated aortic wall tissue (−20.0%; p < 0.05). Replacing GA with EDC as a storage solution led to a further 32.4% ( p < 0.01) mitigation of calcification in Freestyle tissue. Incorporating an intermediate EDC/Jeffamine cross-linking step achieved a distinct additional reduction of calcification by 40.4% ( p < 0.05). Overall, aortic wall calcification was 59.7% ( p < 0.0001) lower if commercial Freestyle tissue underwent an additional EDC/Jeffamine cross-linking step and subsequent storage in EDC. Relative to control GA-fixed tissue, this represented a 67.8% ( p < 0.0001) reduction. Incorporation of AOA was essential for the beneficial effect of the additional EDC/Jeffamine cross-linking step. Conclusions Potentially utilizing both the amino- and the carboxyl moieties of AOA for tissue binding dramatically reduces aortic wall calcification of GA-fixed tissue.

Synthesis of (S)-alpha-amino oleic acid.

An efficient synthesis of (S)-alpha-amino oleic acid was developed. The fully protected FA derivative was obtained in four steps starting from methyl (2S)-2-[bis(tert-butoxycarbonyl)amino]-5-oxopentanoate. These steps are (i) olefination of the starting aldehyde with the appropriate phosphonate anion, (ii) hydrogenation of the double bonds, (iii) controlled reduction of omega-ethyl ester to an aldehyde in the presence of alpha-methyl ester, and (iv) a Wittig reaction of the latter aldehyde with the suitable ylide. Free alpha-amino oleic acid was prepared after deprotection of the amino group followed by saponification in a total yield of 24%. N-tert-Butoxycarbonyl-protected amino oleic acid and the corresponding amino alcohol were prepared in high yield. The structures of the products have been established by various spectroscopic techniques.

Implant technique for the freestyle stentless bioprosthesis

Implant technique for the freestyle stentless bioprosthesis

Mosaic bioprosthesis after 5 years

The Mosaic bioprosthesis is a stented porcine aortic valve, which combines the zero pressure differential fixation technique (by applying equal pressure to the in- and outflow ends of the valve, the aortic root is pressurized to maximize the flow area while no pressure is exerted on the leaflets) and an antimineralization treatment with alpha amino oleic acid for improved tissue durability. The device is in clinical use since February 1994. The purpose of this study was to collect intermediate term data of the Mosaic bioprosthesis in the aortic position to evaluate its clinical and hemodynamic function. From February 1994 to May 1999, 100 patients underwent aortic valve replacement with the Mosaic prosthesis at our department. There were 49 female patients, mean age at implant was 73.4 +/- 7.3 years (range 31 to 87). Concomitant procedures were done in 40%. Preoperative and operative clinical data are shown in Tables 1 and 2. When assessing the size of the bioprosthesis, it is important to use the original Mosaic sizer. Because of the possibility of the so-called supra-x placement, the specific construction of the sizer and the Mosaic valve often allow the implantation of a 1-size larger valve compared to the conventional supra-annular placement. By this a significant increase in the effective flow orifice is possible. This proceeding is depicted in Figure 1. All patients have been anticoagulated with phenprocoumon at least for 3 months postoperatively, INR was aimed at 2.5 to 3.5. Patients have been followed up prospectively, within the initial hospitalization for valve replacement, 6 months postoperatively and at annual intervals including an hematological check and transthoracic echocardiography. The mean follow-up was 2.7 years with a total follow-up of 273.7 patient years. The follow-up was 100% complete. After 5 years the mean systolic pressure gradient was 15.2 +/- 3.0 mm Hg for the 21-mm, 13.1 +/- 4.6 mm Hg for the 23-mm, 10.0 +/- 3.1 mm Hg for the 25-mm valve size, the effective orifice area 1.6 +/- 0.3 cm2 (21-mm), 1.9 +/- 0.3 cm2 (23-mm) and 2.5 +/- 0.8 cm2 (25-mm) (see Table 3). The freedom from prosthesis-related event rates, calculated according to Kaplan-Meier, at 5 years were: 97.3 +/- 1.9% for permanent neurological, 99.0 +/- 1.0% for transient neurological, 95.9 +/- 3.2% for thrombosed prosthesis, 95.6 +/- 2.2% for antithromboembolic related hemorrhage, 96.2 +/- 3.7% for structural valve deterioration, 96.9 +/- 3.0% for non-structural dysfunction, 100% for endocarditis and 92.0 +/- 4.9% for explant (see Table 4). The total operative mortality (within 30 days) was 3.0%, the late postoperative mortality was 4.4% per patient year and included a valve related mortality rate of 0.7%/patient year. In Figure 2 the survival function after aortic valve replacement is depicted, arranged in freedom from all deaths, from Mosaic-related deaths and from Mosaic-related plus sudden/unexplained deaths. Before implantation of the Mosaic bioprosthesis 95% of the patients were in NYHA Classes III and IV, whereas 6 months postoperatively 98% could be classified in NYHA Classes I and II (see Figure 3). In relation to other biological prostheses (Intact, Carpentier-Edwards Pericardial and Porcine, Hancock Modified Orifice, Biocor, Freestyle) the Mosaic bioprosthesis showed very satisfactory and predominantly better hemodynamic results than the compared stented valves and approached the performance of stentless prostheses. The freedom rates from prosthetic-related adverse events of the Mosaic bioprosthesis were at least equivalent to the compared prostheses. However, the satisfactory freedom rates, especially from structural valve deterioration, should be qualified by considering the experience that most incidences appear from the 5th year on after implantation. The clinical and hemodynamic performance of the Mosaic prosthesis has been very satisfactory during the first 5 years after clinical introduction. Further data will be necessary to confirm long-term durability.

Synergistic inhibition of calcification of porcine aortic root with preincubation in FeCl3 and alpha-amino oleic acid in a rat subdermal model.

Postimplant calcific degeneration is a frequent cause of clinical failure of glutaraldehyde crosslinked porcine aortic valve bioprostheses. We demonstrated previously in rat subdermal and circulatory implants that alpha-amino oleic acid used as a bioprosthesis pretreatment was highly effective in mitigating aortic valve cusp but not aortic wall calcification. In this study we investigated the feasibility of synergistically applying two proven anticalcification agents (alpha-amino oleic acid and FeCl3) as pretreatments for mitigating both bioprosthetic cusp and aortic wall calcification. alpha-Amino oleic acid is hypothesized to prevent calcification by disrupting calcium phosphate formation kinetics, whereas suppression of alkaline phosphatase activity and ferric-phosphate complexation at a cellular membrane initiation sites may be important factors in ferric ion's inhibition of calcification. In vivo implant studies (21-day rat subdermal model) indicated that individually FeCl3 (0.01 or 0.1 M for 24 h) or alpha-amino oleic acid (saturated solution) treatments were equally effective in mitigating cuspal calcification (tissue calcium levels: 30.2 +/- 10.2, 29.8 +/- 2.7, and 31.6 +/- 7.8 micrograms/mg tissue, respectively). However, sequential application of first alpha-amino oleic acid and then FeCl3 synergistically reduced aortic wall calcification more effectively than either of the agents alone. The benefit of a synergistic application of two anticalcification treatments, alpha-amino oleic acid and FeCl3, was demonstrated. However, the synergistic effect was observed on aortic wall only at a higher FeCl3 concentration. (i.e., 0.1 M).

Effect of Aoa on Glutaraldehyde-Fixed Bioprosthetic Heart Valve Cusps and Walls: Binding and Calcification Studies

Alpha-aminooleic acid (AOA), a potent, non-toxic and biocompatible anticalcification agent, has been shown to be effective for glutaraldehyde-fixed valves in rat and juvenile sheep models, and is used for the treatment of Medtronic heart valve bioprostheses currently in clinical trials. In the pre-clinical sheep study of a stentless aortic root, the treatment with AOA prevented calcification of the cusps, but not of the wall. The experiments described in this manuscript were designed to investigate a possible relationship between the binding of AOA and the differential treatment efficacy in the cusp and the wall, and to improve the anticalcification effect of the AOA treatment in the wall. Glutaraldehyde-fixed porcine roots were treated with [14C]-AOA for binding studies, and with non-radioactive AOA for calcification studies for rat subdermal implants. The results indicate that a) the AOA treatment did reduce wall calcification, but only temporarily, b) the low efficacy of the AOA treatment on the wall was probably due to the limited penetration of AOA, and c) increasing the volume of the AOA solution during treatment significantly increased the content of AOA in the wall, and significantly decreased wall calcification. This study suggests that AOA efficacy in the wall may be hindered because of the physical characteristics of the wall, and that wall calcification may be prevented by developing methods aimed at increasing AOA penetration into the wall.