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Ann Thorac Surg 2005;79:897-904
© 2005 The Society of Thoracic Surgeons

Original article: Cardiovascular

Prevention of Calcification of Bioprosthetic Heart Valve Cusp and Aortic Wall With Ethanol and Aluminum Chloride

Jocelyn N. Clark, PhDa, Matthew F. Ogle, BSb, Paul Ashworth, BSb, Richard W. Bianco, BSc, Robert J. Levy, MDa,*

a Division of Cardiology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
b St. Jude Medical, Inc, St. Paul, Minnesota
c Department of Surgery, University of Minnesota Medical School, Minneapolis, Minnesota

Accepted for publication August 30, 2004.

* Address reprint requests to Dr Levy, Children's Hospital of Philadelphia, Abramson Research Center, Suite 702, 3615 Civic Center Boulevard, Philadelphia, PA 19104–4318; (E-mail: levyr{at}email.chop.edu).


   Abstract
Top
 Abstract
Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 
BACKGROUND: Calcification is frequently associated with device failure of bioprostheses fabricated from either glutaraldehyde pretreated porcine aortic valves or bovine pericardium. It was hypothesized that differential pretreatment with ethanol-aluminum chloride will prove safe and efficacious for inhibiting the calcification of both the porcine aortic valve bioprosthetic cusp and the aortic wall.

METHODS: Glutaraldehyde-fixed porcine aortic valves were subjected to differential aluminum chloride (AlCl3) and ethanol pretreatment; aortic wall segments were treated exclusively with AlCl3 (0.1 moles/L) for 45 minutes, 6 hours, or 8 hours (groups 3A, B, and C, respectively), followed by valve cusp incubations in ethanol (80%, pH 7.4). Nontreated control bioprosthetic valves were either stent-mounted porcine aortic valve bioprostheses (Carpentier-Edwards, group 1) (Edwards, Santa Anna, CA) or St. Jude Toronto SPV valves (St. Jude Medical, St. Paul, MN) (group 2). Mitral valve replacements were carried out in juvenile sheep for 150 days.

RESULTS: Calcium in cusps from group 3A was 2.84 ± 0.62 mg calcium/g tissue versus control, 22.79 ± 8.46 mg calcium/g tissue, p = 0.04. Valves pretreated with AlCl3 for 45 minutes, 6 hours, and 8 hours had significantly lower levels of calcium in the aortic wall compared to controls (40.38 ± 5.66, 26.77 ± 4.02, and 28.94 ± 8.25 mg calcium/g tissue for groups 3A, 3B, and 3C, respectively, vs 95.47 ± 17.14 mg calcium/g tissue for group 1, p < 0.001, and 133.42 ± 3.96 mg calcium/g tissue for group 2, p < 0.001).

CONCLUSIONS: Differentially applied ethanol and aluminum chloride pretreatment significantly inhibited calcification of both the glutaraldehyde-fixed porcine aortic valve bioprosthetic cusp and the aortic wall.


   Introduction
Top
 Abstract
 Introduction
Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

Drs Ogle and Ashworth disclose that they have a financial relationship with St. Jude Medical, Inc.

 

Stentless porcine aortic valve bioprostheses, which are used for both aortic valve replacement and right ventricular bypass procedures in congenital heart disease surgery, have provided an important alternative to stent-mounted valves because of their more favorable characteristics including smaller annulus profiles and lower pressure gradients [1]. It has been reported that these devices enhance patient survival rate as a consequence of improved flow characteristics and restoration of left ventricular function [2, 3]. Unfortunately, calcification of the aortic wall in the root segment of stentless bioprosthetic valves remains a problem [4–6]. Dystrophic calcification is the most frequent contributing factor to the failure of glutaraldehyde-fixed bioprosthetic valves [7, 8], resulting in stenosis and/or regurgitation, and subsequent valve replacement.

Several antimineralization pretreatments, such as amino-oleic acid (AOA), surfactants, or bisphosphonates have been extensively investigated [9–13]. These reagents were effective in prevention of calcification of the cusps, but not the aortic wall. To overcome this issue, our group has investigated using both ethanol and aluminum chloride (AlCl3) pretreatments to prepare porcine aortic valve bioprostheses [14, 15]. Ethanol prevents mineralization of the cusps by removal of cholesterol and phospholipids and major alterations of collagen intrahelical structural relationships [16, 17]. Aluminum chloride pretreatment prevents aortic wall calcification by inhibition of elastin mineralization due to the following mechanisms: binding of Al to elastin resulting in a permanent protein-structural change conferring calcification resistance, inhibition of alkaline phosphatase activity, diminished upregulation of the extracellular matrix protein, tenascin C, and inhibition of matrix metalloproteinase-mediated elastolysis [18–22].

Previous studies by our group have demonstrated the importance of differential exposure in the use of ethanol-aluminum pretreatments, since cuspal exposure to Al results in exacerbated calcification in sheep mitral valve replacement studies [14, 15]. These prior investigations were for only 90 days duration, and thus in the present studies optimal conditions were studied in 150 day implants in order to assess safety and efficacy.


   Material and Methods
Top
 Abstract
 Introduction
 Material and Methods
Results
 Comment
 Acknowledgments
 References
 
Bioprosthetic Materials and Preparation of Tissue
Porcine aortic valve bioprostheses were fixed with glutaraldehyde and were terminally sterilized under approved conditions at St. Jude Medical (St. Paul, MN). Glutaraldehyde-fixed porcine aortic valves were differentially treated in aqueous aluminum chloride solution (0.1 moles/L), followed by incubation in aqueous 80% ethanol (v/v) in 50 mmol/L N-[2-hydroxyethyl]piperazine-N'-[2-ethanesulfonic acid] (HEPES), pH 7.4, as previously described [14, 15]. Five groups were investigated: group 1 consisted of commercially available glutaraldehyde-fixed porcine aortic stent-mounted Carpentier-Edwards (CE) valves (model 2625, Edwards, Santa Ana, CA); group 2 consisted of porcine aortic stent-mounted St. Jude Toronto stentless porcine valves (TSPV, St. Jude Medical Inc, St. Paul, MN) without ethanol-Al exposure; groups 3A, 3B, and 3C were stent-mounted St. Jude Toronto SPV bioprosthetic valves differentially exposed (aortic wall only) to aluminum chloride (0.1 moles/L, pH 3) for 45 minutes, 6 hours, and 8 hours, respectively, followed by ethanol pretreatment of the valve cusps as stated above as described in detail elsewhere [14, 15]. Differential pretreatment is necessary to avoid Al-induced calcification of the valve cusps [14].

Animal Study Design and Implant Retrieval
All sheep received humane care in compliance with the procedures formulated by the National Institutes of Health (National Institutes of Health Publication No. 85 to 23, revised 1985). Mitral valve replacements were carried out in juvenile (20 weeks old or less) female or neutered male sheep to assess the efficacy of the differential ethanol and aluminum chloride pretreatments compared to controls. Forty-one sheep were obtained from Research Animal Resources (Minneapolis, MN) and were quarantined at the University of Minnesota, Department of Surgery Research Laboratory before undergoing heart valve replacement surgery. The animals were operated under general anesthesia, and then were placed on cardiopulmonary bypass [14]. A left thoracotomy was carried out. Mitral valve replacement was performed [14], and the animals were recovered with a left thoracic chest tube in place, which was removed once postoperative bleeding had stopped, and normal ventilation had resumed. All animals were cared for at Experimental Surgery Services, University of Minnesota (Minneapolis, MN), an American Association of Laboratory Animal Care (AALAC) accredited facility.

Calcification Assessment and Aluminum Toxicity
Cardiac valve bioprostheses retrieved at explant were subjected to immediate pathology assessment and photography, followed by radiographs to assess the gross extent of calcification. Following these analyses, prostheses were preserved in neutral buffered formalin. Samples of the formalin-fixed bioprostheses were allocated for mineral analyses for calcium using acid hydrolysis procedures, followed by atomic absorbance spectroscopy [14]. Other samples of the formalin-fixed bioprostheses were embedded in paraffin and processed for routine microscopy procedures and calcification specific staining, using the von Kossa technique [14]. Animals implanted with valves treated with aluminum chloride were carefully monitored for aluminum levels during the course of the study. Blood samples were taken at various intervals and were assessed by integrated coupled plasma (ICP) atomic spectroscopy analyses [14].

Statistical Analysis
Data are reported as mean ± standard error. Kruskal-Wallis one-way analysis was used to compare changes in calcium, phosphorus, and aluminum levels in different groups, followed by post hoc Dunn's analysis. All statistical analyses were accomplished using SigmaStat 3.0 analysis software (SPSS Inc, Chicago, IL). A p less than or equal to 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Material and Methods
 Results
Comment
 Acknowledgments
 References
 
Overall Surgical Outcomes
Of the 41 animals implanted with either glutaraldehyde-fixed control or ethanol-aluminum chloride pretreated valves, 9 animals died before 21 days postoperation, all due to infection (Table 1). There were also 4 operative deaths caused by complications during surgery. Late deaths (after 21 days) were all associated with marked calcific stenosis of the implanted mitral valve except for a single late sudden death in group 3A (Table 1) due to an arrhythmia. Animals that were electively sacrificed at day 150 were healthy throughout the study. Histology studies of both cusp and aortic wall for group 3 showed no inflammatory or fibrous tissue for the ethanol-aluminum chloride treated valves (data not shown), suggesting no abnormal host response or healing abnormalities. Gross pathology photographs of groups 1 and 2 (CE control and St. Jude TSPV control, respectively) demonstrated calcific deposition in the cusp and aortic wall (Figs 1A and 1B, respectively). Indeed, the retrieved commercial control bioprosthetic valve (group 1) associated with calcification demonstrated findings consistent with cuspal regurgitation, while no visible degeneration or mineralization were detected for group 3A (45-minute aluminum chloride treatment) (Fig 1C).


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  		Table 1. Sheep Mitral Valve Replacement Surgery Outcomes
 


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  		Fig 1. Inhibition of bioprosthetic heart valve calcification by ethanol-aluminum chloride. Gross pathology photographs of bioprosthetic sheep explants with the valves in situ. (A) group 1 (Carpentier-Edwards control), (B) group 2 (St. Jude Toronto stentless porcine valve control), and (C) group 3A (45 minute aluminum chloride treatment) of inflow photographs. Arrows denote calcium phosphate deposits.

 
Sheep Explant Calcification Evaluation
Roentgenogram and calcium analyses using inductively coupled plasma optical emission spectroscopy were used to assess the distribution and extent of calcification throughout the bioprosthetic tissue. Radiographs demonstrated severe cuspal and aortic wall mineralization for control valves (Figs 2A and 2B), while differential treatment with ethanol-aluminum chloride for 45 minutes or longer exhibited lower levels of both cusp and aortic wall mineralization (Fig 2D). No significant cuspal calcification was detected in group 3A, which received differential aluminum chloride pretreatment for 45 minutes (Fig 2C). In addition, calcium and phosphorus levels of cusps and aortic wall samples were determined in both early death and 150-day (sacrificed) animals. As shown in Figure 3, there was a significant reduction in cuspal calcium levels for group 3A compared to groups 2 and 3B (p = 0.04 and p = 0.001, respectively). Surprisingly, 6 hours AlCl3 incubation resulted in significantly higher calcium levels in cusp for group 3B compared to group 3C (p = 0.02). Moreover, phosphorus levels in cusp were also significantly lower in group 3A compared to groups 2 and 3B (p < 0.001). Furthermore, an early death in group 3C (at day 64) demonstrated calcification specific staining (von Kossa) in the cusp, that was not noted in valves retrieved from animals sacrificed at day 150, group 3A (Fig 4). In comparison to controls, the levels of calcium and phosphorus in the aortic wall were significantly less in all valves differentially pretreated with ethanol-aluminum chloride (Fig 5). In accordance to calcium measurements, von Kossa staining in the aortic wall showed intense mineralization for group 2, while group 3A demonstrated only limited positive staining for group 3A (Fig 6) consistent with the calcium/phosphorus results.



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  		Fig 2. Roentgenogram analysis showing inhibition of calcification in bioprosthetic heart valves (sheep explants). (A) group 1 (Carpentier-Edwards control), (B) group 2 (St. Jude Toronto stentless porcine valve control), (C) group 3A (45 minute aluminum chloride treatment), and (D) group 3B (6 hours aluminum chloride treatment) radiographs. Arrows denote calcification, notably absent in (C).

 


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  		Fig 3. Calcium and phosphorus content (mg/g of dry tissue) in bioprosthetic cusps of group 1 (Carpentier-Edwards control), group 2 (Toronto stentless porcine valve control), group 3A (45 minute aluminum chloride treatment), group 3B (6 hours aluminum chloride treatment), and group 3C (8 hours aluminum chloride treatment). Data represented as mean ± standard error. a,bp less than 0.001 compared to groups 2 and 3B, respectively. {square} = calcium; {cjs2113} = phosphorus.

 


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  		Fig 4. Von Kossa staining of bioprosthetic cusps for (A) group 3A (original magnification x100) and (B) early death of group 3B at day 64 with calcification staining red (original magnification x100).

 


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  		Fig 5. Calcium and phosphorus content (mg/g of dry tissue) in bioprosthetic aortic walls (sheep explants) of group 1 (Carpentier-Edwards control), group 2 (Toronto stentless porcine valve control), group 3A (45 minute aluminum chloride treatment), group 3B (6 hours aluminum chloride treatment), and group 3C (8 hours aluminum chloride treatment). Data represented as mean ± standard error. a,bp less than 0.001 compared to groups 1 and 2, respectively, and cp = 0.02 compared to group 1. {square} = calcium; {cjs2113} = phosphorus.

 


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  		Fig 6. Von Kossa calcification staining (red) in bioprosthetic aortic walls for (A) group 2 (original magnification x100) and (B) group 3A (original magnification x100).

 
Aluminum Evaluation
Aluminum levels were measured in both the bioprosthetic cusp and aortic wall of control and aluminum chloride treated valves. In the control (groups 1 and 2) and group 3A cusps, aluminum levels were extremely low, while valves subjected to aluminum chloride for 6 hours and 8 hours showed higher amounts (Fig 7). Indeed, differential pretreatment for 6 hours demonstrated significantly increased Al levels compared to group 3A (p = 0.006). As expected, aluminum levels in the aortic wall were significantly greater for all differentially treated valves compared to control glutaraldehyde-fixed valves (Fig 8). Aluminum content in the aortic wall was increased with extended duration of AlCl3 pretreatment. Furthermore, blood aluminum levels of all animal groups implanted with Al treated valves (Fig 9) did not differ from preimplant levels during the 150 day postoperative period. The highest Al readings in fact were measured before the valves were implanted.



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  		Fig 7. Aluminum content (mg/g of dry tissue) in bioprosthetic cusps of group 1 (Carpentier-Edwards control), group 2 (Toronto stentless porcine valve control), group 3A (45 minute aluminum chloride treatment), group 3B (6 hours aluminum chloride treatment), and group 3C (8 hours aluminum chloride treatment). Data represented as mean ± standard error.

 


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  		Fig 8. Aluminum content (mg/g of dry tissue) in bioprosthetic aortic walls of group 1 (Carpentier-Edwards control), group 2 (Toronto stentless porcine valve control), group 3A (45 minute aluminum chloride treatment), group 3B (6 hours aluminum chloride treatment), and group 3C (8 hours aluminum chloride treatment). Data represented as mean ± standard error. ap less than 0.001 compared to group 1, bp less than 0.001 compared to group 2, cp less than 0.001 compared to group 3A.

 


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  		Fig 9. Aluminum levels (parts per billion, ppb, or ng/mL) in serum of group 3A (45 minute aluminum chloride treatment), group 3B (6 hours aluminum chloride treatment), and group 3C (8 hours aluminum chloride treatment). Data represent mean ± standard error. Preimplant (Preimp), control (cont), and sacrifice (sac) notations represent samples taken approximately 2 weeks before surgery, on the day of surgery, and the day of sacrifice, respectively. {square} = 45 minutes; {cjs2113} = 6 hours; {blacksquare} = 8 hours.

 

   Comment
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
Acknowledgments
 References
 
This study demonstrated that porcine aortic valve bioprostheses subjected to differentially applied ethanol-aluminum chloride was effective in mitigating both valve cuspal and aortic wall calcification. However, increased cuspal calcification was associated with longer durations of AlCl3 pretreatment of the valves as previously noted. The pretreatment of valves with aluminum chloride for 45 minutes showed significantly reduced mineralization. However, extended Al treatment (6 and 8 hours) resulted in cuspal calcification, despite exhibiting beneficial effects on the aortic wall. Previous investigations have demonstrated that bioprosthetic heart valve implants in juvenile sheep result in pathologic calcification that is comparable to that observed clinically [23]. Furthermore, ovine circulatory implants have been proven useful for evaluating anticalcification pretreatments in bioprosthetic heart valve [24]. Thus, in the present long-term circulatory animal study, optimized differential use of ethanol-aluminum chloride pretreatment appears to be highly effective for inhibiting mineralization of both bioprosthetic cusp and aortic wall, and therefore this approach could be efficacious clinically as well.

Several antimineralization approaches for bioprosthetic valves have been investigated [11–13]. Ethanol pretreatment of glutaraldehyde-fixed bioprosthetic valve cusps has been shown to inhibit cuspal calcification in both subdermal implants in rats and in circulatory mitral valve replacements of sheep [16]. The mechanisms of ethanol inhibition may result from its ability to alter multifactorial components in the cusp such as eliminating phospholipids and cholesterol, causing irreversible alterations of collagen intrahelical structural changes, enhancing stability as assessed by increased resistance to collagenase digestion, and directly affecting the calcification process in cusps [16, 17]. However, it has been reported that ethanol pretreatment was efficacious for mitigating cuspal, but not aortic wall, calcification [16, 25]. Alternatively, aluminum chloride pretreatment has been demonstrated to inhibit calcification of both porcine bioprosthetic cusp and aortic wall in rat subdermal model [26–30]. The mechanisms of inhibition are related to the binding of Al to elastin in the aortic wall causing permanent protein-structural change conferring calcification resistance, inhibition of alkaline phosphatase activity and matrix metalloproteinase-mediated elastolysis, and diminishing upregulation of the extracellular matrix protein, tenascin-C [18–22]. Because the mechanisms involved in calcification of the cusp and aortic wall have been found to be different [31], a synergistic use of two anticalcification pretreatments for bioprosthetic aortic valves has been investigated. Furthermore, although the pathologic calcification of bioprosthetic heart valves is nonuniform, the aluminum-ethanol mediated inhibition of calcification reported in the present studies resulted in a relatively uniform absence of mineralization. As the results show, both valve cusps and aortic wall were significantly protected from calcification with the differentially applied ethanol and aluminum chloride (45 minutes, group 3A) pretreatment, as assessed by calcium and phosphorus levels (Figs 2, 3, and 5).

Prior short-term studies have demonstrated that ethanol/AlCl3 must be differentially applied in order to avoid Al contributing to cuspal calcification [14, 15]. In agreement, our results showed similar anticalcification influences on the bioprosthetic valve. Our studies are the first to demonstrate that aluminum chloride exposure to the bioprosthetic valve must be optimized to avoid cusp mineralization. The longer duration of valve pretreatments with aluminum chloride resulted in calcification of the cusp, regardless of whether the pretreatment procedure was applied differentially to the valves. In accordance, the cause of early death in animals, which had valve cusps treated longer than 45 minutes with AlCl3, was a consequence of bioprosthetic cusp calcification. In addition, we found that Al levels were significantly increased in the cusp for the longer aluminum chloride pretreatments. Collectively, these observations suggest that long-term exposure (6 hours and 8 hours) may result in leaching of Al from the aortic wall, leading to the accumulation of Al in the bioprosthetic cusps during storage. Prior work from Carpentier and colleagues [32] found that iron nitrate (Fe(NO3)3)-pretreated bioprosthetic heart valves resulted in rapid Fe leaching and was associated with accelerated calcification of valve cusps in sheep circulatory studies. Work by our group has suggested that low affinity binding of Al to cuspal collagen (versus high affinity to aortic wall elastin) could permit the formation of aluminum phosphate or carbonate precipitates thereby serving as a nucleation site for dystrophic calcific deposits [15].

Compared to other metallic ion pretreatments, aluminum has been shown to be the most effective inhibitor of bioprosthetic aortic wall calcification [33, 34] and alkaline phosphatase activity of bioprosthetic heart tissue in the rat subdermal model [20]. However, it was pertinent to investigate the possibility of adverse effects or toxicity by Al in a long-term implant study. Our findings demonstrated that bioprostheses treated with Al showed normal blood aluminum levels during the course of this study, thus supporting the view that the risk of Al toxicity due to the bioprosthetic implants is low. In agreement, a recent multicenter clinical study [35] has shown that postoperative serum aluminum levels were unchanged from preoperative values over more than two years, in patients that received aortic root bioprostheses pretreated with aluminum. Furthermore, the observed normal Al levels in the present study were many fold below those associated with aluminum-associated toxicity in patients with renal failure [36]. With the increasing use of stentless valves, which have been demonstrated to be useful in circumstances involving valve surgery in the setting of a restrictively small aortic annulus or for right ventricular bypass procedures in congenital heart disease surgery, concerns have been raised about calcification of the aortic wall in the root segment of these devices. A relatively greater portion of the aortic root is exposed to blood compared to stented valves and is susceptible to calcification, which may lead to deleterious events such as stiffening and unfavorably altering the hemodynamics of the valve. Prior reports have demonstrated that mineralization of the bioprosthetic aortic wall occurs with stentless valves [4–6]. It should be noted that previous anticalcification pretreatments for glutaraldehyde-fixed stentless valves were found ineffective in preventing aortic wall calcification [37, 38]. However, as initially reported by our group and others [14, 39, 40], ethanol-aluminum chloride significantly reduces both aortic valve leaflet and aortic root calcification of stentless bioprostheses compared to other treatments. The present studies report the longest circulatory studies to date demonstrating the efficacy of ethanol-aluminum, and also provide strong evidence documenting that this bioprosthetic pretreatment formulation is not associated with any increased systemic aluminum exposure.

Although stentless valve pretreatment protocols were used to prepare the porcine aortic valves (and root segments) in terms of initial fixation and anticalcification pretreatments, the valves once pretreated were nonetheless stent-mounted for use in mitral valve replacements in juvenile sheep, which is the most thoroughly investigated calcification model system. Stent-mounting was necessary because of the technical challenges involved with attempting a stentless bioprosthetic valve replacement in a juvenile sheep. Nevertheless, the approach used in the present protocols resulted in control calcification data (Figs 2 and 3) that were comparable to results noted in clinical bioprosthetic valve explants that had failed due to calcification [41], and thus the present control calcification data support the view that the model approach used was valid. Our present results clearly showed that pretreatment of stent-mounted valves with ethanol-aluminum chloride for 45 minutes exhibited significant antimineralization efficacy. Based on our findings, this pretreatment approach could be used with stentless aortic bioprostheses in order to provide optimal antimineralization conditions for cusps as well as aortic root.

In conclusion, these results have shown that bioprosthetic valves treated with short-term differentially applied ethanol-aluminum chloride demonstrate calcification resistance in 150-day sheep mitral valve replacements in both the bioprosthetic cusp and aortic wall. The bioprosthetic heart valve aluminum content appears not to be associated with a risk for increased systemic aluminum exposure. Thus, this anticalcification approach is effective for maintaining bioprosthetic structural integrity with no significant device related toxicity and therefore may achieve longer bioprosthetic valve durability.


   Acknowledgments
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
References
 
The authors thank Jennifer LeBold for her assistance in the preparation of the manuscript. This research was supported in part by grants RO1-HL74731, RO1-HL64388, and T32-HL07954, from the National Institutes of Health; a grant from St. Jude Medical, Inc; and funding provided by the William J. Rashkind Endowment of the Children's Hospital of Philadelphia.


   References
Top
 Abstract
 Introduction
 Material and Methods
 Results
 Comment
 Acknowledgments
 References
 

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