Quantification of aortic flow by phase-contrast magnetic resonance in patients with bicuspid aortic valve.

AIMS: Bicuspid aortic valve (BAV) causes complex flow patterns in the ascending aorta (AAo), which may compromise the accuracy of flow measurement by phase-contrast magnetic resonance (PC-MR). Therefore, we aimed to assess and compare the accuracy of forward flow measurement in the AAo, where complex flow is more dominant in BAV patients, with flow quantification in the left ventricular outflow tract (LVOT) and the aortic valve orifice (AV), where complex flow is less important, in BAV patients and controls. METHODS AND RESULTS: Flow was measured by PC-MR in 22 BAV patients and 20 controls at the following positions: (i) LVOT, (ii) AV, and (iii) AAo, and compared with the left ventricular stroke volume (LVSV). The correlation between the LVSV and the forward flow in the LVOT, the AV, and the AAo was good in BAV patients (r = 0.97/0.96/0.93; P < 0.01) and controls (r = 0.96/0.93/0.93; P < 0.01). However, in relation with the LVSV, the forward flow in the AAo was mildly underestimated in controls and much more in BAV patients [median (inter-quartile range): 9% (4%/15%) vs. 22% (8%/30%); P < 0.01]. This was not the case in the LVOT and the AV. The severity of flow underestimation in the AAo was associated with flow eccentricity. CONCLUSION: Flow measurement in the AAo leads to an underestimation of the forward flow in BAV patients. Measurement in the LVOT or the AV, where complex flow is less prominent, is an alternative means for quantifying the systolic forward flow in BAV patients.

Mechanical strain induces the production of spheroid mineralized microparticles in the aortic valve through a RhoA/ROCK-dependent mechanism

Calcific aortic valve disease (CAVD) is a chronic disorder characterized by an abnormal mineralization of the leaflets, which is accelerated in bicuspid aortic valve (BAV). It is suspected that mechanical strain may promote/enhance mineralization of the aortic valve. However, the effect of mechanical strain and the involved pathways during mineralization of the aortic valve remains largely unknown. Valve interstitial cells (VICs) were isolated and studied under strain conditions. Human bicuspid aortic valves were examined as a model relevant to increase mechanical strain. Cyclic strain increased mineralization of VICs by several-fold. Scanning electron microscope (SEM) and energy dispersive X-ray (EDX) analyses revealed that mechanical strain promoted the formation of mineralized spheroid microparticles, which coalesced into larger structure at the surface of apoptotic VICs. Apoptosis and mineralization were closely associated with expression of ENPP1. Inhibition of ENPP1 greatly reduced mineralization of VIC cultures. Through several lines of evidence we showed that mechanical strain promoted the export of ENPP1-containing vesicles to the plasma membrane through a RhoA/ROCK pathway. Studies conducted in human BAV revealed the presence of spheroid mineralized structures along with the expression of ENPP1 in areas of high mechanical strain. Mechanical strain promotes the production and accumulation of spheroid mineralized microparticles by VICs, which may represent one important underlying mechanism involved in aortic valve mineralization. RhoA/ROCK-mediated export of ENPP1 to the plasma membrane promotes strain-induced mineralization of VICs.

Transcatheter Aortic Valve Replacement in Bicuspid Aortic Valve Disease.

BACKGROUND Limited information exists describing the results of transcatheter aortic valve (TAV) replacement in patients with bicuspid aortic valve (BAV) disease (TAV-in-BAV). OBJECTIVES This study sought to evaluate clinical outcomes of a large cohort of patients undergoing TAV-in-BAV. METHODS We retrospectively collected baseline characteristics, procedural data, and clinical follow-up findings from 12 centers in Europe and Canada that had performed TAV-in-BAV. RESULTS A total of 139 patients underwent TAV-in-BAV with the balloon-expandable transcatheter heart valve (THV) (n = 48) or self-expandable THV (n = 91) systems. Patient mean age and Society of Thoracic Surgeons predicted risk of mortality scores were 78.0 ± 8.9 years and 4.9 ± 3.4%, respectively. BAV stenosis occurred in 65.5%, regurgitation in 0.7%, and mixed disease in 33.8% of patients. Incidence of type 0 BAV was 26.7%; type 1 BAV was 68.3%; and type 2 BAV was 5.0%. Multislice computed tomography (MSCT)-based TAV sizing was used in 63.5% of patients (77.1% balloon-expandable THV vs. 56.0% self-expandable THV, p = 0.02). Procedural mortality was 3.6%, with TAV embolization in 2.2% and conversion to surgery in 2.2%. The mean aortic gradient decreased from 48.7 ± 16.5 mm Hg to 11.4 ± 9.9 mm Hg (p < 0.0001). Post-implantation aortic regurgitation (AR) grade ≥2 occurred in 28.4% (19.6% balloon-expandable THV vs. 32.2% self-expandable THV, p = 0.11) but was prevalent in only 17.4% when MSCT-based TAV sizing was performed (16.7% balloon-expandable THV vs. 17.6% self-expandable THV, p = 0.99). MSCT sizing was associated with reduced AR on multivariate analysis (odds ratio [OR]: 0.19, 95% confidence intervals [CI]: 0.08 to 0.45; p < 0.0001). Thirty-day device safety, success, and efficacy were noted in 79.1%, 89.9%, and 84.9% of patients, respectively. One-year mortality was 17.5%. Major vascular complications were associated with increased 1-year mortality (OR: 5.66, 95% CI: 1.21 to 26.43; p = 0.03). CONCLUSIONS TAV-in-BAV is feasible with encouraging short- and intermediate-term clinical outcomes. Importantly, a high incidence of post-implantation AR is observed, which appears to be mitigated by MSCT-based TAV sizing. Given the suboptimal echocardiographic results, further study is required to evaluate long-term efficacy.

Clinical and haemodynamic outcomes in 658 patients receiving the Perceval sutureless aortic valve: early results from a prospective European multicentre study (the Cavalier Trial)†.

OBJECTIVES The aim of the Cavalier trial was to evaluate the safety and performance of the Perceval sutureless aortic valve in patients undergoing aortic valve replacement (AVR). We report the 30-day clinical and haemodynamic outcomes from the largest study cohort with a sutureless valve. METHODS From February 2010 to September 2013, 658 consecutive patients (mean age 77.8 years; 64.4% females; mean logistic EuroSCORE 10.2%) underwent AVR in 25 European Centres. Isolated AVRs were performed in 451 (68.5%) patients with a less invasive approach in 219 (33.3%) cases. Of the total, 40.0% were octogenarians. Congenital bicuspid aortic valve was considered an exclusion criterion. RESULTS Implantation was successful in 628 patients (95.4%). In isolated AVR through sternotomy, the mean cross-clamp time and the cardiopulmonary bypass (CPB) time were 32.6 and 53.7 min, and with the less invasive approach 38.8 and 64.5 min, respectively. The 30-day overall and valve-related mortality rates were 3.7 and 0.5%, respectively. Valve explants, stroke and endocarditis occurred in 0.6, 2.1 and in 0.1% of cases, respectively. Preoperative mean and peak pressure gradients decreased from 44.8 and 73.24 mmHg to 10.24 and 19.27 mmHg at discharge, respectively. The mean effective orifice area improved from 0.72 to 1.46 cm(2). CONCLUSIONS The current 30-day results show that the Perceval valve is safe (favourable haemodynamic effect and low complication rate), and can be implanted with a fast and reproducible technique after a short learning period. Short cross-clamp and CPB times were achieved in both isolated and combined procedures. The Perceval valve represents a promising alternative to biological AVR, especially with a less invasive approach and in older patients.

Proteomic alterations in heat shock protein 27 and identification of phosphoproteins in ascending aortic aneurysm associated with bicuspid and tricuspid aortic valve

Whether or not there are molecular differences, at the intra- and extracellular level, between aortic dilatation in patients with bicuspid (BAV) and those with a tricuspid aortic valve (TAV) has remained controversial for years. We have performed 2-dimensional gel electrophoresis and mass spectrometry coupled with dephosphorylation and phosphostaining experiments to reveal and define protein alterations and the high abundant structural phosphoproteins in BAV compared to TAV aortic aneurysm samples. 2-D gel patterns showed a high correlation in protein expression between BAV and TAV specimens (n=10). Few proteins showed significant differences, among those a phosphorylated form of heat shock protein (HSP) 27 with significantly lower expression in BAV compared to TAV aortic samples (p=0.02). The phosphoprotein tracing revealed four different phosphoproteins including Rho GDP dissociation inhibitor 1, calponin 3, myosin regulatory light chain 2 and four differentially phosphorylated forms of HSP27. Levels of total HSP27 and dually phosphorylated HSP27 (S78/S82) were investigated in an extended patient cohort (n=15) using ELISA. Total HSP27 was significantly lower in BAV compared to TAV patients (p=0.03), with no correlation in levels of phospho-HSP27 (S78/S82) (p=0.4). Western blots analysis showed a trend towards lower levels of phospho-HSP27 (S78) in BAV patients (p=0.07). Immunohistochemical analysis revealed that differences in HSP27 occur in the cytoplasma of VSMC's and not extracellularly. Alterations in HSP27 may give early evidence for intracellular differences in aortic aneurysm of patients with BAV and TAV. Whether HSP27 and the defined phosphoproteins have a specific role in BAV associated aortic dilatation remains to be elucidated.

Treatment of congenital aortic valve stenosis: impact of the Ross operation.

GOAL: To evaluate the impact of the Ross operation, recently (1997) introduced in our unit, for the treatment of patients with congenital aortic valve stenosis. METHODS: The period from January 1997 to December 2000 was compared with the previous 5 years (1992-96). Thirty-seven children (< 16 yrs) and 49 young adults (16-50 yrs) with congenital aortic valve stenosis underwent one of these treatments: percutaneous balloon dilatation (PBD), aortic valve commissurotomy, aortic valve replacement and the Ross operation. The Ross operation was performed in 16 patients, mean age 24.5 yrs (range 9-46 yrs) with a bicuspid stenotic aortic valve, 7/10 adults with calcifications, 2/10 adults with previous aortic valve commissurotomy, 4/6 children with aortic regurgitation following PBD, and 1/6 children who had had a previous aortic valve replacement with a prosthetic valve and aortic root enlargement. RESULTS: PBD was followed by death in two neonates (fibroelastosis); all other children survived PBD. Although there were no deaths, PBD in adults was recently abandoned, owing to unfavourable results. Aortic valve commissurotomy showed good results in children (no deaths). Aortic valve replacement, although associated with good results (no deaths), has been recently abandoned in children in favour of the Ross operation. Over a mean follow-up of 16 months (2-40 months) all patients are asymptomatic following Ross operation, with no echocardiographic evidence of aortic valve regurgitation in 10/16 patients and with trivial regurgitation in 6/16 patients. CONCLUSIONS: The approach now for children and young adults with congenital aortic valve stenosis should be as follows: (1) PBD is the first choice in neonates and infants; (2) Aortic valve commissurotomy is the first choice for children, neonates and infants after failed PBD; (3) The Ross operation is increasingly used in children after failed PBD and in young adults, even with a calcified aortic valve.

Open issues in transcatheter aortic valve implantation. Part 1: patient selection and treatment strategy for transcatheter aortic valve implantation.

An exponential increase in the use of transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis has been witnessed over the recent years. The current article reviews different areas of uncertainty related to patient selection. The use and limitations of risk scores are addressed, followed by an extensive discussion on the value of three-dimensional imaging for prosthesis sizing and the assessment of complex valve anatomy such as degenerated bicuspid valves. The uncertainty about valvular stenosis severity in patients with a mismatch between the transvalvular gradient and the aortic valve area, and how integrated use of echocardiography and computed tomographic imaging may help, is also addressed. Finally, patients referred for TAVI may have concomitant mitral regurgitation and/or coronary artery disease and the management of these patients is discussed.

Genomics to elucidate the molecular basis of calcific aortic valve disease

Le rétrécissement valvulaire aortique (RVA) est causé par une calcification et une fibrose progressive de la valve aortique. Le risque de développer la maladie augmente avec l’âge. À cause de l’augmentation de l’espérance de vie, le RVA est devenu un problème de santé publique. Le RVA est fatal en absence de traitement médical. Actuellement, la chirurgie est le seul traitement pour le stade sévère de la maladie, mais près de 50% des individus avec RVA n’y sont pas éligibles, principalement due à la présence de comorbidités. Plusieurs processus biologiques ont été associés à la maladie, mais les voies moléculaires spécifiques et les gènes impliqués dans le développement et la progression du RVA ne sont pas connus. Il est donc urgent de découvrir les gènes de susceptibilité pour le RVA afin d’identifier les personnes à risque ainsi que les biomarqueurs et les cibles thérapeutiques pouvant mener au développement de médicaments pour inverser ou limiter la progression de la maladie. L’objectif de cette thèse de doctorat était d’identifier la base moléculaire du RVA. Des approches modernes en génomique, incluant l’étude de gènes candidats et le criblage génomique par association (GWAS), ont été réalisées à l’aide de collections d’ADN provenant d’un grand nombre de patients bien caractérisés pour le RVA. Des études complémentaires en transciptomique ont comparé le profil d’expression global des gènes entre des valves calcifiées et non-calcifiées à l’aide de biopuces à ADN et de séquençage de l’ARN. Une première étude a identifié des variations dans le gène NOTCH1 et suggère pour la première fois la présence d’un polymorphisme commun dans ce gène conférant une susceptibilité au RVA. La deuxième étude a combiné par méta-analyse deux GWAS de patients provenant de la ville de Québec et Paris (France) aux données transcriptomiques. Cette étude de génomique intégrative a confirmé le rôle de RUNX2 dans le RVA et a permis l’identification d’un nouveau gène de susceptibilité, CACNA1C. Les troisième et quatrième études sur l’expression des gènes ont permis de mieux comprendre les bases moléculaires de la calcification des valves aortiques bicuspides et ainsi d’identifier de nouvelles cibles thérapeutiques pour le RVA. Les données générées par ce projet sont la base de futures découvertes importantes qui permettront d’améliorer les options de traitement et la qualité de vie des patients atteints du RVA.

The silent and apparent neurological injury in transcatheter aortic valve implantation study (SANITY) : concept, design and rationale

Background The incidence of clinically apparent stroke in transcatheter aortic valve implantation (TAVI) exceeds that of any other procedure performed by interventional cardiologists and, in the index admission, occurs more than twice as frequently with TAVI than with surgical aortic valve replacement (SAVR). However, this represents only a small component of the vast burden of neurological injury that occurs during TAVI, with recent evidence suggesting that many strokes are clinically silent or only subtly apparent. Additionally, insult may manifest as slight neurocognitive dysfunction rather than overt neurological deficits. Characterisation of the incidence and underlying aetiology of these neurological events may lead to identification of currently unrecognised neuroprotective strategies. Methods The Silent and Apparent Neurological Injury in TAVI (SANITY) Study is a prospective, multicentre, observational study comparing the incidence of neurological injury after TAVI versus SAVR. It introduces an intensive, standardised, formal neurologic and neurocognitive disease assessment for all aortic valve recipients, regardless of intervention (SAVR, TAVI), valve-type (bioprosthetic, Edwards SAPIEN-XT) or access route (sternotomy, transfemoral, transapical or transaortic). Comprehensive monitoring of neurological insult will also be recorded to more fully define and compare the neurological burden of the procedures and identify targets for harm minimisation strategies. Discussion The SANITY study undertakes the most rigorous assessment of neurological injury reported in the literature to date. It attempts to accurately characterise the insult and sustained injury associated with both TAVI and SAVR in an attempt to advance understanding of this complication and associations thus allowing for improved patient selection and procedural modification.

Pathobiological Aspects of Nonreheumatic Aortic Valve Stenosis

Aortic valve stenosis (AS) is an active disease process akin to atherosclerosis, with chronic inflammation, lipid accumulation, extracellular matrix remodeling, fibrosis, and extensive calcification of the valves being characteristic features of the disease. The detailed mechanisms and pathogenesis of AS are still incompletely understood, however, and pharmacological treatments targeted toward components of the disease are not currently available. In this thesis project, my coworkers and I studied stenotic aortic valves obtained from 86 patients undergoing valve replacement for clinically significant AS. Non-stenotic control valves (n=17) were obtained from patients undergoing cardiac transplantation or from organ donors without cardiac disease. We identified a novel inflammatory factor, namely mast cell, in stenotic aortic valves and present evidence showing that this multipotent inflammatory cell may participate in the pathogenesis of AS. Using immunohistochemistry and double immunofluorescence stainings, we found that a considerable number of mast cells accumulate in stenotic valves and, in contrast to normal valves, the mast cells in diseased valves were in an activated state. Moreover, valvular mast cells contained two effective proteases, chymase and cathepsin G, which may participate in adverse remodeling of the valves either by inducing fibrosis (chymase and cathepsin G) or by degrading elastin fibers in the valves (cathepsin G). As chymase and cathepsin G are both capable of generating the profibrotic peptide angiotensin II, we also studied the expression and activity of angiotensin-converting enzyme (ACE) in the valves. Using RT-PCR, imunohistochemistry, and autoradiography, we observed a significant increase in the expression and activity of ACE in stenotic valves. Besides mast cell-derived cathepsin G, aortic valves contained other elastolytic cathepsins (S, K, and V). Using immunohistochemistry, RT-PCR, and fluorometric microassay, we showed that the expression and activity of these cathepsins were augmented in stenotic valves. Furthermore, in stenotic but not in normal valves, we observed a distinctive pattern of elastin fiber degradation and disorganization. Importantly, this characteristic elastin degradation observed in diseased valves could be mimicked by adding exogenous cathepsins to control valves, which initially contained intact elastin fibers. In stenotic leaflets, the collagen/elastin ratio was increased and correlated positively with smoking, a potent AS-accelerating factor. Indeed, cigarette smoke could also directly activate cultured mast cells and fibroblasts. Next, we analyzed the expression and activity of neutral endopeptidase (NEP), which parallels the actions of ACE in degrading bradykinin (BK) and thus inactivates antifibrotic mechanisms in tissues. Real-time RT-PCR and autoradiography revealed NEP expression and activity to be enhanced in stenotic valves compared to controls. Furthermore, both BK receptors (1 and 2) were present in aortic valves and upregulated in stenotic leaflets. Isolated valve myofibroblasts expressed NEP and BK receptors, and their upregulation occurred in response to inflammation. Finally, we observed that the complement system, a source of several proinflammatory mediators and also a potential activator of valvular mast cells, was activated in stenotic valves. Moreover, receptors for the complement-derived effectors C3a and C5a were expressed in aortic valves and in cultured aortic valve myofibroblasts, in which their expression was induced by inflammation as well as by cigarette smoke. In conclusion, our findings revealed several novel mechanisms of inflammation (mast cells and mast cell-derived mediators, complement activation), fibrosis (ACE, chymase, cathepsin G, NEP), and elastin fiber degradation (cathepsins) in stenotic aortic valves and highlighted these effectors as possible pathogenic contributors to AS. These results support the notion of AS as an active process with inflammation and extracellular matrix remodeling as its key features and identify possible new targets for medical therapy in AS.

Primary isolated aortic valve surgery in octogenarians.

We reviewed our surgery registry, to identify predictive risk factors for operative results, and to analyse the long-term survival outcome in octogenarians operated for primary isolated aortic valve replacement (AVR). A total of 124 consecutive octogenarians underwent open AVR from January 1990 to December 2005. Combined procedures and redo surgery were excluded. Selected variables were studied as risk factors for hospital mortality and early neurological events. A follow-up (FU; mean FU time: 77 months) was obtained (90% complete), and Kaplan-Meier plots were used to determine survival rates. The mean age was 82+/-2.2 (range: 80-90 years; 63% females). Of the group, four patients (3%) required urgent procedures, 10 (8%) had a previous myocardial infarction, six (5%) had a previous coronary angioplasty and stenting, 13 patients (10%) suffered from angina and 59 (48%) were in the New York Heart Association (NYHA) class III-IV. We identified 114 (92%) degenerative stenosis, six (5%) post-rheumatic stenosis and four (3%) active endocarditis. The predicted mortality calculated by logistic European System for Cardiac Operative Risk Evaluation (EuroSCORE) was 12.6+/-5.7%, and the observed hospital mortality was 5.6%. Causes of death included severe cardiac failure (four patients), multi-organ failure (two) and sepsis (one). Complications were transitory neurological events in three patients (2%), short-term haemodialysis in three (2%), atrial fibrillation in 60 (48%) and six patients were re-operated for bleeding. Atrio-ventricular block, myocardial infarction or permanent stroke was not detected. The age at surgery and the postoperative renal failure were predictors for hospital mortality (p value <0.05), whereas we did not find predictors for neurological events. The mean FU time was 77 months (6.5 years) and the mean age of surviving patients was 87+/-4 years (81-95 years). The actuarial survival estimates at 5 and 10 years were 88% and 50%, respectively. Our experience shows good short-term results after primary isolated standard AVR in patients more than 80 years of age. The FU suggests that aortic valve surgery in octogenarians guarantees satisfactory long-term survival rates and a good quality of life, free from cardiac re-operations. In the era of catheter-based aortic valve implantation, open-heart surgery for AVR remains the standard of care for healthy octogenarians.