Decellularized tissue-engineered heart valves calcification: what do animal and clinical studies tell us?

Abstract

Cardiovascular diseases are the first cause of death worldwide. Among different heart malfunctions, heart valve failure due to calcification is still a challenging problem. While drug-dependent treatment for the early stage calcification could slow down its progression, heart valve replacement is inevitable in the late stages. Currently, heart valve replacements involve mainly two types of substitutes: mechanical and biological heart valves. Despite their significant advantages in restoring the cardiac function, both types of valves suffered from serious drawbacks in the long term. On the one hand, the mechanical one showed non-physiological hemodynamics and the need for the chronic anticoagulation therapy. On the other hand, the biological one showed stenosis and/or regurgitation due to calcification. Nowadays, new promising heart valve substitutes have emerged, known as decellularized tissue-engineered heart valves (dTEHV). Decellularized tissues of different types have been widely tested in bioprosthetic and tissue-engineered valves because of their superior biomechanics, biocompatibility, and biomimetic material composition. Such advantages allow successful cell attachment, growth and function leading finally to a living regenerative valvular tissue in vivo. Yet, there are no comprehensive studies that are covering the performance of dTEHV scaffolds in terms of their efficiency for the calcification problem. In this review article, we sought to answer the question of whether decellularized heart valves calcify or not. Also, which factors make them calcify and which ones lower and/or prevent their calcification. In addition, the review discussed the possible mechanisms for dTEHV calcification in comparison to the calcification in the native and bioprosthetic heart valves. For this purpose, we did a retrospective study for all the published work of decellularized heart valves. Only animal and clinical studies were included in this review. Those animal and clinical studies were further subcategorized into 4 categories for each depending on the effect of decellularization on calcification. Due to the complex nature of calcification in heart valves, other in vitro and in silico studies were not included. Finally, we compared the different results and summed up all the solid findings of whether decellularized heart valves calcify or not. Based on our review, the selection of the proper heart valve tissue sources (no immunological provoking residues), decellularization technique (no damaged exposed residues of the decellularized tissues, no remnants of dead cells, no remnants of decellularizing agents) and implantation techniques (avoiding suturing during the surgical implantation) could provide a perfect anticalcification potential even without in vitro cell seeding or additional scaffold treatment.

Sevelamer Attenuates Bioprosthetic Heart Valve Calcification

“…A relationship between inflammation and calcification has been demonstrated in many studies (3,5). Macrophage is the most found immune cell in BHVs, whereas T lymphocytes and B lymphocytes, neutrophils, and eosinophils are less frequent.…”

“…Our study showed that sevelamer does not affect body weight and food intake, corroborating previous studies ( 13 ). Bone parameters were not measured in this study, but according to the literature, sevelamer cannot reduce bone density ( 5 , 14 ). Since sevelamer cannot be absorbed in the gut and cannot induce hypophosphatemia and hypocalcemia, we can conclude that sevelamer is a safe treatment to attenuate BHV calcification.…”

“…The immune response to xenograft antigens such as galactose-α-1,3-galactose (α-Gal) and N-glycolylneuraminic acid (NeuGc), which are not expressed in humans, contributes to BHV calcification. Clinical studies also documented the relationship between BHV calcification and impaired lipid metabolism ( 3 , 5 ).…”

“…Several techniques are being developed to avoid BHV calcifications ( 5 , 15 , 24 ), including a new crosslinking method to stabilize more ECM components, a decellularization technique to eliminate cellular debris, proper heart valve tissue sources from gene knockout animals with no immunological antigens, such as α-Gal and NeuGc, and new implantation techniques. However, considering that millions of BHVs have already been implanted, a therapy for BHV calcification prevention is required.…”

“…The general mechanisms of the native valve and BHV calcification seem to be related. Calcium and phosphate in the blood can form crystal cores in BHVs, which play important roles in BHV calcification ( 5 ). These findings indicated that attenuating the calcification might prolong the durability of BHVs ( 3 ).…”