Adult Aortic Valve Research Articles

Programmable Melt Electrowriting to Engineer Soft Connective Tissues with Prescribed, Biomimetic, Biaxial Mechanical Properties

AbstractAppropriate load‐bearing function of soft connective tissues is provided by their nonlinear and often anisotropic mechanics. Recapitulating such complex mechanical behavior in tissue‐engineered structures is particularly crucial, as deviation from native tissue mechanics can trigger pathological biomechanical pathways, causing adverse tissue remodeling and dysfunction. Here, a novel method combining computational modeling, melt electrowriting (MEW), and design of experiments (DOE) is reported to generate scaffolds composed of sinusoidal fibers with prescribed biaxial mechanical properties, recapitulating the distinct nonlinear, anisotropic stress–strain behavior of three model tissues: adult aortic valve, pediatric pulmonary valve, and pediatric pericardium. Finite element analysis is used to efficiently optimize scaffold architecture over a broad parameter space, representing up to 65 conditions, to define MEW print parameters to achieve polycaprolactone scaffolds with target mechanical properties. Architectural parameters are further optimized experimentally using DOE and regression to account for uncertainties involved in the simulation, yielding functional scaffolds with accurate, prescribed mechanics. The prescribed architecture also primarily governs the mechanics of hybrid structures generated by casting cell‐laden fibrin hydrogel within the scaffolds. This high‐fidelity approach recapitulates biaxial mechanical properties over a broad range of mechanical nonlinearity and anisotropy and is generalizable for programmed biofabrication in a variety of tissue engineering applications.

NOTCH Signaling in Aortic Valve Development and Calcific Aortic Valve Disease.

NOTCH intercellular signaling mediates the communications between adjacent cells involved in multiple biological processes essential for tissue morphogenesis and homeostasis. The NOTCH1 mutations are the first identified human genetic variants that cause congenital bicuspid aortic valve (BAV) and calcific aortic valve disease (CAVD). Genetic variants affecting other genes in the NOTCH signaling pathway may also contribute to the development of BAV and the pathogenesis of CAVD. While CAVD occurs commonly in the elderly population with tri-leaflet aortic valve, patients with BAV have a high risk of developing CAVD at a young age. This observation indicates an important role of NOTCH signaling in the postnatal homeostasis of the aortic valve, in addition to its prenatal functions during aortic valve development. Over the last decade, animal studies, especially with the mouse models, have revealed detailed information in the developmental etiology of congenital aortic valve defects. In this review, we will discuss the molecular and cellular aspects of aortic valve development and examine the embryonic pathogenesis of BAV. We will focus our discussions on the NOTCH signaling during the endocardial-to-mesenchymal transformation (EMT) and the post-EMT remodeling of the aortic valve. We will further examine the involvement of the NOTCH mutations in the postnatal development of CAVD. We will emphasize the deleterious impact of the embryonic valve defects on the homeostatic mechanisms of the adult aortic valve for the purpose of identifying the potential therapeutic targets for disease intervention.

Asporin Reduces Adult Aortic Valve Interstitial Cell Mineralization Induced by Osteogenic Media and Wnt Signaling Manipulation In Vitro.

Worldwide, calcific aortic valve disease is one of the leading causes of morbidity and mortality among patients with cardiac abnormalities. Aortic valve mineralization and calcification are the key events of adult calcific aortic valve disease manifestation and functional insufficiency. Due to heavy mineralization and calcification, adult aortic valvular cusps show disorganized and dispersed stratification concomitant with deposition of calcific nodules with severely compromised adult valve function. Interestingly, shared gene regulatory pathways are identified between bone-forming cells and heart valve cells during development. Asporin, a small leucine-rich proteoglycan (43 kDa), acts to inhibit mineralization in periodontal ligament cells and is also detected in normal murine adult aortic valve leaflets with unknown function. Therefore, to understand the Asporin function in aortic cusp mineralization and calcification, adult avian aortic valvular interstitial cell culture system is established and osteogenesis has been induced in these cells successfully. Upon induction of osteogenesis, reduced expression of Asporin mRNA and increased expression of bone and osteogenesis markers are detected compared to cells maintained without osteogenic induction. Importantly, treatment with human recombinant Asporin protein reduces the mineralization level in osteogenic media-induced aortic valvular interstitial cells with the concomitant decreased level of Wnt/β-catenin signaling. Overall, all these data are highly indicative that Asporin might be a novel biomolecular target to treat patients of calcific aortic valve disease over current cusp replacement surgery.

A case of adult unicuspid aortic valve stenosis that underwent emergent aortic valve replacement for severe heart failure

A case of adult unicuspid aortic valve stenosis that underwent emergent aortic valve replacement for severe heart failure

Corrigendum: Postnatal and Adult Aortic Heart Valves Have Distinctive Transcriptional Profiles Associated With Valve Tissue Growth and Maintenance Respectively

[This corrects the article DOI: 10.3389/fcvm.2018.00030.].

Postnatal and Adult Aortic Heart Valves HaveDistinctive Transcriptional Profiles Associated With Valve Tissue Growth and Maintenance Respectively.

Heart valves are organized connective tissues of high mechanical demand. They open and close over 100,000 times a day to preserve unidirectional blood flow by maintaining structure-function relationships throughout life. In affected individuals, structural failure compromises function and often leads to regurgitant blood flow and progressive heart failure. This is most common in degenerative valve disease due to age-related wear and tear, or congenital malformations. At present, the only effective treatment of valve disease is surgical repair or replacement and this is often impermanent and requires anti-coagulation therapy throughout life. Therefore, there is a critical need to discover new alternatives. A promising therapeutic area is tissue regeneration and in non-valvular tissues this requires a tightly regulated genetic “growth program” involving cell proliferation. To explore this in heart valves, we performed RNA-seq analysis to compare transcriptional profiles of aortic valve tissue isolated from mice during stages of growth (postnatal day (PND) 2) and adult maintenance (4 months). Data analysis reveals distinct mRNA profiles at each time point and pathway ontology identifies associated changes in biological functions. The PND2 aortic valve is characterized by extensive cell proliferation and expression of mRNAs related to the extracellular matrix (ECM). At 4 months, proliferation is not significant and a differential set of ECM-related genes are expressed. Interestingly there is enrichment of the defense response biological process at this later time point. Together, these data highlight the unique transcriptome of the postnatal valve during stages of growth and maturation, as well as biological functions associated with adult homeostatic valves. These studies create a platform for future work exploring the molecular programs altered in the onset of heart valve disease after birth and provide insights for the development of mechanistic-based therapies.

Cerebral perfusion monitoring in adult patients following cardiac surgery: an observational study

Background: Following adult cardiac surgery, often difficult to detect fluctuations in regional cerebral perfusion can contribute to strokes. Optimal cerebral perfusion remains elusive and traditional monitoring strategies do not consistently identify acute changes. Non-invasive cerebral oximetry may detect perfusion variations.Objective: To assess the feasibility of postoperative non-invasive cerebral oximetry monitoring.Methods: Non-invasive cerebral oximetry was performed on adult aortic valve surgery patients in a cardiac surgical intensive care unit. Monitoring feasibility was assessed using an investigator-developed, data extraction tool.Results: Non-invasive cerebral oximetry was completed in 94% of patients. Sixty percent had values that fell below pre-set ischemic threshold. Nurses reported monitoring was feasible, and they perceived identifying deleterious cerebral perfusion trends may improve patient care.Conclusions: Prevalence of low cerebral oximetry values underscores the importance of increasing sensitivity of monitoring tools. Further evaluation is required to assess this modality and the role of nurses in optimizing neurocognitive outcomes.Impact statement: Cerebral oximetry monitoring may help identify adult patients at risk of neurological complications after cardiac surgery, and as a consequence initiate definitive therapeutic strategies.

Aortic Valve Surgery in the Pediatric Population

In this paper, current approaches to pediatric aortic valve surgery are discussed. While many pediatric aortic valve operations are palliative until an adult-sized prosthetic can fit, some recent advances in adult aortic valve repair techniques can be applied to the pediatric population yielding more definitive repair. Systematic analysis of the valve pathology is necessary to decide on the appropriate operation and refer patients to surgeons with the appropriate expertise. The Ross operation remains an ideal operation for pediatric patients with significant aortic valve disease and a competent pulmonic valve, given that it allows the autograft to grow with the child. Depending on aortic valve pathology, those with regurgitation secondary to aneurysmal dilation of the aorta may be candidates for various valve-sparing techniques. Critical congenital aortic stenosis may be managed via balloon valvuloplasty or surgical valvotomy depending on the specific scenario. Valve replacement is not ideal in the pediatric population, particularly if the patient is not full-grown, but can be necessary.

Invited Commentary

In this study by Deng and colleagues [1Deng X.-S. Meng X. Zeng Q.C. Fullerton D. Mitchell M. Jaggers J. Adult aortic valve interstitial cells have greater responses to Toll-like receptor 4 stimulation.Ann Thorac Surg. 2015; 99: 62-71Abstract Full Text Full Text PDF Scopus (8) Google Scholar], age-dependent differences in toll-like receptor-4 (TLR4) response to stimulation with lipopolysaccharide (LPS) were examined in pediatric and adult aortic valve interstitial cells (AVICs) in an effort to identify underlying mechanisms that contribute to the pathogenesis of calcific aortic valve disease. The AVIC is the principal cell type in the aortic valve leaflet and has been implicated in the disease process by undergoing phenotypic changes that result in the activation of proinflammatory and proosteogenic responses that activate bone-formation signaling pathways and ultimately result in stiffening of valve leaflets. The key findings of this study demonstrated that the p38 mitogen activated protein kinase (p38MAPK) and nuclear factor-κ B (NFκB) inflammatory pathways were elevated in adult AVICs in response to LPS but not in pediatric AVICs. This was associated with an increase in protein levels of proosteogenic mediators intercellular adhesion molecule 1 (ICAM-1), bone morphogenetic protein-2 (BMP-2), and alkaline phosphatase (ALP). Importantly, the authors demonstrated that the difference in age-dependent response to LPS was not due to changes in TLR4 protein levels (the primary cellular receptor for LPS) but to the loss of tyrosine phosphorylation of signal transducer and activator of transcription-3 (STAT3). This was further supported by elegant work showing that the inhibition of STAT3 in young AVICs, by use of either a pharmacologic STAT3 inhibitor or a short-hairpin ribonucleic acid designed to suppress STAT3 translation, could mimic the LPS response of adult AVICs. Together, these studies suggest that age-dependent differences in TLR4 signaling alter the response of adult AVICs to inflammatory stimuli, and they implicate the loss of STAT3 activation as one mechanism that may contribute to the pathogenesis of calcific aortic valve disease. The authors speculate that the inhibition of TLR4 activation may show a clinical benefit. However, while there has been ongoing interest in the identification of small molecule inhibitors of TLR4, only a limited number of candidate drugs have made it into clinical trials, highlighting the difficulty of targeting a key component of the innate immune system. Further elucidation of the signaling pathways leading to STAT3 activation in pediatric AVICs may help identify the age-dependent defects in STAT3 activation and may identify alternative mechanisms that could be targeted for therapeutic advantage. For example, targeting the activation of AVICs through the inhibition of pathways that mediate cellular phenotype change, such as BMP-2, may attenuate the pathologic responses to TLR4 stimulation in adult cells. This is a very interesting and thought-provoking area of study, and Deng and colleagues should be congratulated for their excellent work. Adult Aortic Valve Interstitial Cells Have Greater Responses to Toll-Like Receptor 4 StimulationThe Annals of Thoracic SurgeryVol. 99Issue 1PreviewAortic valve interstitial cells (AVICs) have been implicated in the pathogenesis of calcific aortic valve disease. Signal transducer and activator of transcription 3 (Stat3) possesses antiinflammatory effects. Given that calcification occurs in adult valves, we hypothesized that AVICs from adult valves more likely undergo a proosteogenic phenotypic change than those from pediatric valves and that may be related to different Stat3 activation in the response of those two age groups to toll-like receptor 4 (TLR4). Full-Text PDF

Loss of β-catenin promotes chondrogenic differentiation of aortic valve interstitial cells.

The Wnt/β-catenin signaling pathway has been implicated in human heart valve disease and is required for early heart valve formation in mouse and zebrafish. However, the specific functions of Wnt/β-catenin signaling activity in heart valve maturation and maintenance in adults have not been determined previously. Here, we show that Wnt/β-catenin signaling inhibits Sox9 nuclear localization and proteoglycan expression in cultured chicken embryo aortic valves. Loss of β-catenin in vivo in mice, using Periostin(Postn)Cre-mediated tissue-restricted loss of β-catenin (Ctnnb1) in valvular interstitial cells, leads to the formation of aberrant chondrogenic nodules and induction of chondrogenic gene expression in adult aortic valves. These nodular cells strongly express nuclear Sox9 and Sox9 downstream chondrogenic extracellular matrix genes, including Aggrecan, Col2a1, and Col10a1. Excessive chondrogenic proteoglycan accumulation and disruption of stratified extracellular matrix maintenance in the aortic valve leaflets are characteristics of myxomatous valve disease. Both in vitro and in vivo data demonstrate that the loss of Wnt/β-catenin signaling leads to increased nuclear expression of Sox9 concomitant with induced expression of chondrogenic extracellular matrix proteins. β-Catenin limits Sox9 nuclear localization and inhibits chondrogenic differentiation during valve development and in adult aortic valve homeostasis.

Abstract 332: Loss of beta-catenin Leads to Induction of a Chondrogenic Phenotype in Adult Mouse Heart Aortic Valves

Objectives: Altered Wnt/beta-catenin signaling has been implicated in human heart valve disease; however, a causal relation has not been established. This study is aimed at determining the role of Wnt/beta-catenin signaling in adult valve homeostasis and disease. In endochondral bone development, Wnt/beta-catenin signaling inhibits early chondrogenesis and promotes osteogenesis. Therefore, we hypothesize that loss of Wnt/beta-catenin signaling promotes chondrogenic differentiation of valvular interstitial cells (VICs) resembling myxomatous valve disease. Methods & Results: Periostin (Postn)Cre was used for conditional loss of beta-catenin (Ctnnb1) specifically in VICs in mice. PostnCre is active in valve mesenchymal progenitors by embryonic day (E)13.5, therefore bypassing requirements for beta-catenin in endothelial-to-mesenchymal transition and endocardial cushion formation. Histology of adult heart valves was analyzed by Masson’s Trichrome and Movat’s Pentachrome staining, and the expression of extracellular matrix (ECM) genes was examined at both mRNA and protein level. Heart valve development appears normal at both fetal and neonatal stages with loss of beta-catenin. However proteoglycan-rich nodules form in adult aortic valves (AoVs) lacking beta-catenin at 3 months with 100% penetrance. These nodular cells are enlarged and express nuclear Sox9 and chondrogenic ECM genes, including Aggrecan, Collagen type 2 (Col1) and Col10, reminiscent of hypertrophic cartilage. Fibrillar collagens 1 and 3, as well as Versican, are excluded from the nodules, accompanied by abnormal ECM deposition throughout the AoV leaflets. Likewise, treatment of cultured porcine aortic VICs with the Wnt pathway inhibitor XAV also induces Aggrecan and Col2 gene expression in vitro. This work demonstrates that beta-catenin is required for the maintenance of normal ECM deposition and composition in adult mice, and, therefore, is indispensible for adult heart valve homeostasis. Conclusions: We have demonstrated that beta-catenin is a key factor in maintaining normal valve ECM organization in adult AoV. In the absence of beta-catenin, VICs are susceptible to chondrogenic differentiation related to myxomatous valve disease.

Conserved Transcriptional Regulatory Mechanisms in Aortic Valve Development and Disease

There is increasing evidence for activation of developmental transcriptional regulatory pathways in heart valve disease. Here, we review molecular regulatory mechanisms involved in heart valve progenitor development, leaflet morphogenesis, and extracellular matrix organization that also are active in diseased aortic valves. These include regulators of endothelial-to-mesenchymal transitions, such as the Notch pathway effector RBPJ, and the valve progenitor markers Twist1, Msx1/2, and Sox9. Little is known of the potential reparative or pathological functions of these developmental mechanisms in adult aortic valves, but it is tempting to speculate that valve progenitor cells could contribute to repair in the context of disease. Likewise, loss of either RBPJ or Sox9 leads to aortic valve calcification in mice, supporting a potential therapeutic role in prevention of disease. During aortic valve calcification, transcriptional regulators of osteogenic development are activated in addition to valve progenitor regulatory programs. Specifically, the transcription factor Runx2 and its downstream target genes are induced in calcified valves. Runx2 and osteogenic genes also are induced with vascular calcification, but activation of valve progenitor markers and the cellular context of expression are likely to be different for valve and vascular calcification. Additional research is necessary to determine whether developmental mechanisms contribute to valve repair or whether these pathways can be harnessed for new treatments of heart valve disease.

Abstract 18574: Examination of a Highly Penetrant Mouse Model of Bicuspid Aortic Valve Demonstrates that Endothelial Notch1 is Required for Proper Morphogenesis of the Aortic Valve

Bicuspid aortic valve (BAV) is the most common type of cardiac malformation with an estimated prevalence of 1-2% in the population. BAV results in significant morbidity as it is one of the leading causes of valve stenosis and regurgitation in adults. We previously reported that mutations in the signaling and transcriptional regulator, NOTCH1 , were a cause of BAV in non-syndromic autosomal-dominant human pedigrees. The Notch signaling pathway is critical for multiple cell differentiation processes, and Notch1 is expressed in the developing and adult aortic valve. Recently, we have generated a new highly penetrant mouse model of aortic valve malformations using Notch1 haploinsufficient mice that are backcrossed in a Nos3-null background. Notch1 and Nos3 compound mutant adult mice ( Notch1 +/- ;Nos3 -/- ) display a nearly 100% incidence of BAV. The aortic valves of adult mutant mice are thickened and have associated stenosis and regurgitation. We have also found that by postnatal day 10, compound mutant mice suffer ~50% lethality compared to NOS3 -/- littermates. Here, we have examined Notch1 +/- ;Nos3 -/- embryos at serial timepoints to elucidate the mechanisms underlying BAV. Examination at embryonic day 18.5 (E18.5) demonstrated normal Mendelian ratios and histologic examination revealed thickened, malformed valve leaflets accompanied by other outflow tract abnormalities in NOS3 -/- ;Notch1 -/+ mice, likely contributing to the neonatal lethality. Further investigation at E13.5 and E15.5 indicated that the NOS3 -/- ;Notch1 -/+ aortic valve leaflets were significantly thicker than controls, suggesting that outflow tract cushion formation and early remodeling may be affected. In addition, we have generated mice are null for Nos3 and haploinsufficient for Notch1 in endothelial-derived cells using mice harboring a Notch1 -floxed allele and Tie2-Cre mice. Our preliminary results indicate that NOS3 -/- ; Notch1 fl/+ ;Tie2Cre + mice recapitulate the NOS3 -/- ;Notch1 -/+ cardiac phenotype and suggest that endothelial Notch1 is required for proper development of the aortic valve. Overall our data indicate that loss of endothelial Notch1 results in abnormal remodeling of the outflow tract cushions and contributes to BAV.

Endothelial nitric oxide signaling regulates Notch1 in aortic valve disease

The mature aortic valve is composed of a structured trilaminar extracellular matrix that is interspersed with aortic valve interstitial cells (AVICs) and covered by endothelium. Dysfunction of the valvular endothelium initiates calcification of neighboring AVICs leading to calcific aortic valve disease (CAVD). The molecular mechanism by which endothelial cells communicate with AVICs and cause disease is not well understood. Using a co-culture assay, we show that endothelial cells secrete a signal to inhibit calcification of AVICs. Gain or loss of nitric oxide (NO) prevents or accelerates calcification of AVICs, respectively, suggesting that the endothelial cell-derived signal is NO. Overexpression of Notch1, which is genetically linked to human CAVD, retards the calcification of AVICs that occurs with NO inhibition. In AVICs, NO regulates the expression of Hey1, a downstream target of Notch1, and alters nuclear localization of Notch1 intracellular domain. Finally, Notch1 and NOS3 (endothelial NO synthase) display an in vivo genetic interaction critical for proper valve morphogenesis and the development of aortic valve disease. Our data suggests that endothelial cell-derived NO is a regulator of Notch1 signaling in AVICs in the development of the aortic valve and adult aortic valve disease.

Periostin Expression is Altered in Aortic Valves in Smad6 Mutant Mice.

Smad6 is known to predominantly inhibit BMP signaling by negatively regulating the BMP signaling process. Therefore, Smad6 mutation potentially provides an important genetic model for investigating the role of BMP signaling in vivo. Periostin is a 90-kDA secreted extracellular matrix (ECM) protein and implicated in cardiac valve progenitor cell differentiation, maturation and adult aortic valve calcification in mice. We have previously reported periostin expression patterns during AV valve development in mice. Because periostin can play critical roles in aortic valve interstitial cell differentiation and can be correlated with adult valve disease pathogenesis, in the present study we specifically focused on periostin expression during outflow tract (OT) development and its expression within the adult mouse valves. We previously reported that periostin expression in valve progenitor cells was altered by exogenously adding BMP-2 in culture. In this study, we investigated whether expression of periostin and other valvulogenic ECM proteins was altered in Smad6-mutant newborn mice in vivo. Periostin protein was localized within OT during embryonic development in mice. At embryonic day (ED) 13.5, robust periostin expression was detected within the developing pulmonary trunk and developing pulmonary and aortic valves. Periostin expression remained intense in pulmonary and aortic valves up to the adult stage. Our immunohistochemical and immunointensity analyses revealed that periostin expression was significantly reduced in the aortic valves in Smad6−/− neonatal hearts. Versican expression was also significantly reduced in Smad6−/− aortic valves, whereas, hyaluronan deposition was not significantly altered in the Smad6−/− neonatal valves. Expression of periostin and versican was less prominently affected in AV valves compared to the aortic valves, suggesting that a cell lineage/origin-dependent response to regulatory molecules may play a critical role in valve interstitial cell development and ECM protein expression.

Inhibitory role of Notch1 in calcific aortic valve disease.

Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism.

Do bigger hospitals or busier surgeons do better adult aortic or mitral valve operations?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was whether there is a relationship between hospital or surgeon volume (SV) and postoperative outcome in adult aortic or mitral valve surgery. One hundred and sixty papers were found using the specified search strategy, of which seven papers represented the best evidence to answer this question. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, methodology scores, study weaknesses and results are tabulated. Outcomes assessed by these studies were variable; four papers used mortality, one paper used morbidity, one paper used care processes and one paper examined all the above-mentioned outcomes. Six papers investigated the effect of hospital volume (HV) on outcome whilst only one paper assessed the effect of both HV and SV on outcome. The type of valve operated on was also mixed; two papers studied aortic valve only, one paper studied mitral valve only and four papers studied both valves. The methodological quality and validity of each study was assessed by a predefined scoring system. The median total quality score was modest and not strong enough to support the conclusions reported by these studies. In addition, volume-outcome relationship can be affected by several factors related to patient, surgeon and hospital. These factors have not been considered in depth by the mentioned papers. However, there may be a positive relationship between hospital procedural volume and mortality which is more likely to be mediated by SV, and there is also a potential relationship with the rate of mitral valve repair and the use of bio-prosthetic valves in elderly patients. We conclude that regionalisation of adult aortic or mitral valve surgery based on such a limited number of modest quality studies would be an indefensible policy. The implementation of such a scheme can have many clinical, practical, economical and political consequences which have not been examined prospectively until today. Furthermore, the relationship between volume and other outcomes rather than mortality needs further assessment.

Stentless versus Stented Bioprosthetic Aortic Valves

: This meta-analysis sought to determine whether stentless bioprosthetic valves improve clinical and resource outcomes compared with stented valves in patients undergoing aortic valve replacement. : A comprehensive search was undertaken to identify all randomized and nonrandomized controlled trials comparing stentless to stented bioprosthetic valves in patients undergoing aortic valve replacement available up to March 2008. The primary outcomes were clinical and resource outcomes in randomized controlled trial (RCT). Secondary outcomes clinical and resource outcomes in nonrandomized controlled trial (non-RCT). Odds ratios (OR), weighted mean differences (WMD), or standardized mean differences and their 95% confidence intervals (CI) were analyzed as appropriate. : Seventeen RCTs published in 23 articles involving 1317 patients, and 14 non-RCTs published in 18 articles involving 2485 patients were included in the meta-analysis. For the primary analysis of randomized trials, mortality for stentless versus stented valve groups did not differ at 30 days (OR 1.36, 95% CI 0.68-2.72), 1 year (OR 1.01, 95% CI 0.55-1.85), or 2 to 10 years follow-up (OR 0.82, 95% CI 0.50-1.33). Aggregate event rates for all-cause mortality at 30 days were 3.7% versus 2.9%, at 1 year were 5.5% versus 5.9% and at 2 to 10 years were 17% versus 19% for stentless versus stented valve groups, respectively. Stroke or neurologic complications did not differ between stentless (3.6%) and stented (4.0%) valve groups. Risk of prosthesis-patient mismatch was numerically lower in the stentless group (11.0% vs. 31.3%, OR 0.30, 95% CI 0.05-1.66), but this parameter was reported in few trials and did not reach statistical significance. Effective orifice area index was significantly greater for stentless aortic valve compared with stented valves at 30 days (WMD 0.12 cm/m), at 2 to 6 months (WMD 0.15 cm/m), and at 1 year (WMD 0.26 cm/m). Mean gradient at 1 month was significantly lower in the stentless valve group (WMD -6 mm Hg), at 2 to 6 month follow-up (WMD -4 mm Hg,), at 1 year follow-up (WMD -3 mm Hg) and up to 3 year follow-up (WMD -3 mm Hg) compared with the stented valve group. Although the left ventricular mass index was generally lower in the stentless group versus the stented valve group, the aggregate estimates of mean difference did not reach significance during any time period of follow-up (1 month, 2-6 months, 1 year, and 8 years). : Evidence from randomized trials shows that subcoronary stentless aortic valves improve hemodynamic parameters of effective orifice area index, mean gradient, and peak gradient over the short and long term. These improvements have not led to proven impact on patient morbidity, mortality, and resource-related outcomes; however, few trials reported on clinical outcomes beyond 1 year and definitive conclusions are not possible until sufficient evidence addresses longer-term effects.

Opposing actions of Notch1 and VEGF in post-natal cardiac valve endothelial cells

The endothelium of the cardiac valves is unique compared the rest of the vasculature in its ability to undergo an endothelial-to-mesenchymal transformation (EMT) in vitro in response to transforming growth factor-β (TGF-β). EMT is a critical event during embryonic valve development, and both VEGF-A and Notch1 have been shown to function in this process. Here we investigate the effects of VEGF-A and Notch1 on EMT in clonal endothelial cell (EC) populations isolated from adult aortic valve leaflets. VEGF-A inhibited TGF-β-induced EMT. Endothelial growth, however, was not affected by VEGF-A or TGF-β. A positive role for Notch1 was revealed in three experiments: (1) TGF-β induced Notch1 mRNA in valve ECs, (2) a γ-secretase inhibitor of Notch1 signaling blocked EMT, and (3) overexpression of a ligand-independent form of Notch1 induced EMT. These results demonstrate, for the first time, that VEGF-A and Notch1 play opposing roles in regulating EMT in post-natal valve endothelium.

Risk-corrected impact of mechanical versus bioprosthetic valves on long-term mortality after aortic valve replacement

Choice of a mechanical or biologic valve in aortic valve replacement remains controversial and rotates around different complications with different time-related incidence rates. Because serious complications will always "spill over" into mortality, our aim was to perform a meta-analysis on overall mortality after aortic valve replacement from series with a maximum follow-up of at least 10 years to determine the age- and risk factor-corrected impact of currently available mechanical versus stented bioprosthetic valves. Following a formal study protocol, we performed a dedicated literature search of publications during 1989 to 2004 and included articles on adult aortic valve replacement with a mechanical or stented bioprosthetic valve if age, mortality statistics, and prevalences of well-known risk factors could be extracted. We used standard and robust regression analyses of the case series data with valve type as a fixed variable. We could include 32 articles with 15 mechanical and 23 biologic valve series totaling 17,439 patients and 101,819 patient-years. The mechanical and biologic valve series differed in regard to mean age (58 vs 69 years), mean follow-up (6.4 vs 5.3 years), coronary artery bypass grafting (16% vs 34%), endocarditis (7% vs 2%), and overall death rate (3.99 vs 6.33 %/patient-year). Mean age of the valve series was directly related to death rate with no interaction with valve type. Death rate corrected for age, New York Heart Association classes III and IV, aortic regurgitation, and coronary artery bypass grafting left valve type with no effect. Included articles that abided by current guidelines and compared a mechanical and biologic valve found no differences in rates of thromboembolism. There was no difference in risk factor-corrected overall death rate between mechanical or bioprosthetic aortic valves irrespective of age. Choice of prosthetic valve should therefore not be rigorously based on age alone. Risk of bioprosthetic valve degeneration in young and middle-aged patients and in the elderly and old with a long life expectancy would be an important factor because risk of stroke may primarily be related to patient factors.