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Open in new tab Download slide OBJECTIVES Hypercholesterolaemia and obesity are risk factors for the development of calcified aortic valve disease and common comorbidities in respective patients. Peroxisome proliferator-activated receptor gamma activation has been shown to reduce the progression of native aortic valve sclerosis, while its effect on bioprosthetic valve degeneration is yet unknown. This project aims to analyse the impact of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the degeneration of biological aortic valve conduits in an implantation model in obese and hypercholesterolaemic rats. METHODS Cryopreserved allogenic rat aortic valve conduits (n  = 40) were infrarenally implanted into Wistar rats on high-fat (34.6%) diet. One cohort was treated with pioglitazone (75 mg/kg chow; n  = 20, group PIO) and compared to untreated rats (n  = 20, group control). After 4 or 12 weeks, conduits were explanted and analysed by (immuno-)histology and real-time polymerase chain reaction. RESULTS A significantly decreased intima hyperplasia occurred in group PIO compared to control after 4 (P  = 0.014) and 12 weeks (P  = 0.045). Calcification of the intima was significantly decreased in PIO versus control at 12 weeks (P  = 0.0001). No significant inter-group differences were shown for media calcification after 4 and 12 weeks. Echocardiographically, significantly lower regurgitation through the implanted aortic valve conduit was observed in PIO compared to control after 4 (P  = 0.018) and 12 weeks (P  = 0.0004). Inflammatory activity was comparable between both groups. CONCLUSIONS Systemic peroxisome proliferator-activated receptor gamma activation decreases intima hyperplasia and subsequent intima calcification of cryopreserved allografts in obese, hypercholesterolaemic recipients. Additionally, it seems to inhibit functional impairment of the implanted aortic valve. Further preclinical studies are required to determine the long-term impact of peroxisome proliferator-activated receptor gamma agonists on graft durability. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide Open in new tab Download slide OBJECTIVES Intima hyperplasia is a major issue of biological cardiovascular grafts resulting in progressive in vivo degeneration that particularly decreases the durability of coronary and peripheral vascular bypasses. Previously, dichloroacetate (DCA) has been reported to prevent the formation of hyperplastic intima in injured arteries. In this study, the effect of DCA on the neointima formation and degeneration of decellularized small-caliber implants was investigated in a rat model. METHODS Donor rat aortic grafts (n  = 22) were decellularized by a detergent-based technique, surface-coated with fibronectin (50 µl ml−1, 24 h incubation) and implanted via anastomoses to the infrarenal aorta of the recipients. Rats in the DCA group (n  = 12) received DCA via drinking water during the whole follow-up period (0.75 g l−1), while rats without DCA treatment served as controls (n  = 10). At 2 (n  = 6 + 5) and 8 (n  = 6 + 5) weeks, the grafts were explanted and examined by histology and immunofluorescence. RESULTS Systemic DCA treatment inhibited neointima hyperplasia, resulting in a significantly reduced intima-to-media ratio (median 0.78 [interquartile range, 0.51–1.27] vs 1.49 [0.67–2.39] without DCA, P  < 0.001). At 8 weeks, neointima calcification, as assessed by an established von Kossa staining-based score, was significantly decreased in the DCA group (0 [0–0.25] vs 0.63 [0.06–1.44] without DCA, P  < 0.001). At 8 weeks, explanted grafts in both groups were luminally completely covered by an endothelial cell layer. In both groups, inflammatory cell markers (CD3, CD68) proved negative. CONCLUSIONS Systemic DCA treatment reduces adverse neointima hyperplasia in decellularized small-caliber arterial grafts, while allowing for rapid re-endothelialization. Furthermore, DCA inhibits calcification of the implants. [ABSTRACT FROM AUTHOR]

A 61-year-old male who underwent aortic valve replacement with an Inspiris Resilia® aortic bioprosthetic through an upper partial sternotomy due to severe aortic valve stenosis was presented 1 year later to our hospital suffering from dyspnoea and chest pain. The transthoracic echocardiography demonstrated moderate haemodynamic structural valve deterioration with a mean gradient of 29 mmHg and a valve area of 0.9 cm2. Due to relatively high-risk of reoperation, valve-in-valve transcatheter aortic valve replacement with Sapien 3® 29 mm, followed by balloon valvuloplasty, was successfully performed. To the best of our knowledge, this is the first published case of valve-in-valve transcatheter aortic valve replacement into a degenerated Inspiris Resilia® aortic valve. [ABSTRACT FROM AUTHOR]

Calcific aortic valve disease (CAVD) is characterized by valvular fibrosis and calcification and driven by differentiating valvular interstitial cells (VICs). Expression data from patient biopsies suggest that transforming growth factor (TGF)-β1 is implicated in CAVD pathogenesis. However, CAVD models using isolated VICs failed to deliver clear evidence on the role of TGF-β1. Thus, employing cultures of aortic valve leaflets, we investigated effects of TGF-β1 in a tissue-based three-dimensional (3-D) CAVD model. We found that TGF-β1 induced phosphorylation of Mothers against decapentaplegic homolog (SMAD) 3 and expression of SMAD7, indicating effective downstream signal transduction in valvular tissue. Thus, TGF-β1 increased VIC contents of rough endoplasmic reticulum, Golgi, and secretory vesicles as well as tissue levels of RNA and protein. In addition, TGF-β1 raised expression of proliferation marker cyclin D1, attenuated VIC apoptosis, and upregulated VIC density. Moreover, TGF-β1 intensified myofibroblastic VIC differentiation as evidenced by increased α-smooth muscle actin and collagen type I along with diminished vimentin expression. In contrast, TGF-β1 attenuated phosphorylation of SMAD1/5/8 and upregulation of β-catenin while inhibiting osteoblastic VIC differentiation as revealed by downregulation of osteocalcin expression, alkaline phosphatase activity, and extracellular matrix incorporation of hydroxyapatite. Collectively, these effects resulted in blocking of valvular tissue calcification and associated disintegration of collagen fibers. Instead, TGF-β1 induced development of fibrosis. Overall, in a tissue-based 3-D CAVD model, TGF-β1 intensifies expressional and proliferative activation along with myofibroblastic differentiation of VICs, thus triggering dominant fibrosis. Simultaneously, by inhibiting SMAD1/5/8 activation and canonical Wnt/β-catenin signaling, TGF-β1 attenuates osteoblastic VIC differentiation, thus blocking valvular tissue calcification. These findings question a general phase-independent CAVD-promoting role of TGF-β1. NEW & NOTEWORTHY Employing aortic valve leaflets as a tissue-based three-dimensional disease model, our study investigates the role of transforming growth factor (TGF)-β1 in calcific aortic valve disease pathogenesis. We find that, by activating Mothers against decapentaplegic homolog 3, TGF-β1 intensifies expressional and proliferative activation along with myofibroblastic differentiation of valvular interstitial cells, thus triggering dominant fibrosis. Simultaneously, by inhibiting activation of Mothers against decapentaplegic homolog 1/5/8 and canonical Wnt/β-catenin signaling, TGF-β1 attenuates apoptosis and osteoblastic differentiation of valvular interstitial cells, thus blocking valvular tissue calcification. These findings question a general phase-independent calcific aortic valve disease-promoting role of TGF-β1.