Anatomical and clinical predictors of valve dysfunction and aortic dilation in bicuspid aortic valve disease.

OBJECTIVE: Bicuspid aortic valve (BAV) is associated with early valvular dysfunction and proximal aorta dilation with high heterogeneity. This study aimed to assess the determinants of these complications. METHODS: Eight hundred and fifty-two consecutive adults diagnosed of BAV referred from cardiac outpatient clinics to eight echocardiographic laboratories of tertiary hospitals were prospectively recruited. Exclusion criteria were aortic coarctation, other congenital disorders or intervention. BAV morphotype, significant valve dysfunction and aorta dilation (≥2 Z-score) at sinuses and ascending aorta were established. RESULTS: Three BAV morphotypes were identified: right-left coronary cusp fusion (RL) in 72.9%, right-non-coronary (RN) in 24.1% and left-non-coronary (LN) in 3.0%. BAV without raphe was observed in 18.3%. Multivariate analysis showed aortic regurgitation (23%) to be related to male sex (OR: 2.80, p<0.0001) and valve prolapse (OR: 5.16, p<0.0001), and aortic stenosis (22%) to BAV-RN (OR: 2.09, p<0.001), the presence of raphe (OR: 2.75, p<0.001), age (OR: 1.03; p<0.001), dyslipidaemia (OR: 1.77, p<0.01) and smoking (OR: 1.63, p<0.05). Ascending aorta was dilated in 76% without differences among morphotypes and associated with significant valvular dysfunction. By contrast, aortic root was dilated in 34% and related to male sex and aortic regurgitation but was less frequent in aortic stenosis and BAV-RN. CONCLUSIONS: Normofunctional valves are more prevalent in BAV without raphe. Aortic stenosis is more frequent in BAV-RN and associated with some cardiovascular risk factors, whereas aortic regurgitation (AR) is associated with male sex and sigmoid prolapse. Although ascending aorta is the most commonly dilated segment, aortic root dilation is present in one-third of patients and associated with AR. Remarkably, BAV-RL increases the risk for dilation of the proximal aorta, whereas BAV-RN spares this area.

Increased blood levels of transforming growth factor ß in patients with aortic dilatation.

OBJECTIVES: Recent studies have shown that patients with syndromic thoracic aortic aneurysm, particularly patients with bicuspid aortic valve, have increased blood levels of transforming growth factor ß1 (TGF-ß1), indicating this molecule as a prognostic biomarker. However, it is not known whether TGF-ß1 is also elevated in the blood of patients with tricuspid aortic valve and aortic dilatation. METHODS: We analysed the plasma levels of TGF-ß1 in 52 patients with tricuspid or bicuspid aortic valve and with normal or dilated ascending aorta who underwent cardiac surgery in our hospital. RESULTS: TGF-ß1 blood level was significantly increased two-fold in patients with tricuspid aortic valve and dilated aorta compared to patients with tricuspid aortic valve and normal aorta. CONCLUSIONS: Our results suggest that TGF-ß1 blood levels may serve as a prognostic biomarker for patients with syndromic and non-syndromic thoracic aortic aneurysm. Further studies with larger cohorts of patients should be performed to confirm these results.

Fibrillin 2 is upregulated in the ascending aorta of patients with bicuspid aortic valve.

OBJECTIVES: Bicuspid aortic valve (BAV) is the most prevalent congenital cardiac malformation, frequently associated with aortic dilatation (AD). The molecular mechanisms involved in AD and its aetiological link with BAV formation are poorly understood. Altered fibrillin-1 (FBN1) and metalloprotease-2, -9 (MMP2,9) protein activities have been suggested to be involved in BAV aortopathy. In addition, FBN2 participates in embryonic valve formation, but its possible involvement in BAV-associated AD has never been explored. In this report, we evaluate the expression levels of MMP2,9 and FBN1,2 in the ascending aorta of patients with normal or dilated aortas and with tricuspid aortic valve (TAV) or BAV, using appropriate tissue-specific reference genes. METHODS: Gene expression was quantified by real-time quantitative polymerase chain reaction in 52 patients, using one or three reference genes previously validated in the same patient population. RESULTS: FBN2 expression was significantly increased in the aortas of patients with BAV compared with individuals with TAV (0.178 ± 0.042 vs 0.096 ± 0.021, P = 0.015), whereas differences in FBN1 did not reach statistical significance (1.946 ± 0.228 vs 1.430 ± 0.114, P = 0.090). When four groups of samples were considered, FBN2 expression was significantly higher in patients with BAV and AD compared with patients with TAV and AD (0.164 ± 0.035 vs 0.074 ± 0.027, P = 0.040). No significant differences were found when FBN1/FBN2 ratio, and MMP2 and MMP9 expression levels were analysed. No linear relationship between aortic diameter and gene expression levels were found. CONCLUSIONS: BAV patients have an increased FBN (especially FBN2) gene expression level in the ascending aorta, irrespective of dilatation, whereas MMP expression does not change significantly. These results add a new piece of information to the pathophysiology of BAV disease and point to FBN2 as a new molecular player.

Infective endocarditis in patients with bicuspid aortic valve: Clinical characteristics, complications, and prognosis. / Endocarditis infecciosa sobre válvula aórtica bicúspide: características clínicas, complicaciones y pronóstico.

INTRODUCTION: Bicuspid aortic valve (BAV) is the most frequent congenital cardiac disease. It is associated to a higher risk of cardiovascular complications, including infective endocarditis (IE). METHODS: Retrospective, observational and single centre study that included all patients with IE diagnosed between 1996 and 2014. An analysis was made of the epidemiological, clinical, microbiological and echocardiographic data, complications during hospital admission, need for surgery, in-hospital mortality, and 1-year follow-up. Cases with endocarditis on prosthetic valves or other locations were excluded, as well as those for which the aortic valve morphology had not been accurately defined. A comparative statistical analysis was performed between BAV and tricuspid (TAV). RESULTS: Of a total of 328 cases with IE, 118 (35.67%) were on aortic valve, with 18 (16.22%) of them being BAV. The BAV cases were younger than TAV (51±19.06 vs. 60.83±15.73 years, P=.021) and they had less comorbidity (Charlson 0.67±0.77 vs. 1.44±1.64, P=.03).). There was a higher tendency of Staphylococcal origin (38.9 vs. 21.5%, P=.137), and 55.6% showed peri-valvular complications (TAV 16.1%, P=.001), in particular, abscesses (38.9 vs.16.1%, P=.047). BAV was the only predictive factor of peri-valvular complications (OR 7.87, 95% CI; 2.38-26.64, P=.001). Patients with BAV had more surgery during their admission (83.3 vs. 44.1%, P=.004), had less in-hospital mortality, with no statistical significance (5.6 vs. 25.8%, P=.069), and 1-year survival was significantly superior (93.8 vs 69.3%, P=.048). CONCLUSIONS: Patients with IE on BAV are young, with low comorbidity. They frequently present with peri-valvular complications and they often require early surgery. Compared to TAV cases, in-hospital mortality is lower and 1-year survival is significantly higher.

Válvula aórtica bicúspide: resultados a largo plazo de la cirugía reparadora / Long-term Results with Reconstructiva Surgery of the Bicuspid Aortic Valve

Introducción: La válvula aórtica bicúspide es la anomalía congénita cardíaca más frecuente. En pacientes con requerimienro de cirugía, el tratamiento tradicional ha sido la sustitución valvular. La introducción del concepto de reparación de la válvula aórtica bicúspide ha llevado a nuestro grupo a reproducir las técnicas de reparación, las cuales se han estandarizado y aplicado de manera homogénea en nuestras instituciones. Objetivos: Revisar la experiencia conjunta de tres centros, con la presentación de los resultados a mediano y a largo plazos de la reparación valvular. Material y métodos: Entre octubre de 1995 y febrero de 2013 se intervinieron 666 pacientes con válvulas bicúspides e insuficiencia aórtica y/o aneurisma de la aorta. De ellos, 254 presentaban insuficiencia aórtica aislada y 412, aneurisma o disección. Se reconstruyó la válvula en todos los pacientes (en 254 como procedimiento aislado, en 281 "remodelación de la raíz", en 129 remodelación de la unión sinotubular y en 2 "reimplantación"). Resultados: La mortalidad fue de 3/666 (0,5%): 1/254 (0,4%) tras reparación valvular aislada y 2/410 (0,5%) tras reparación más reemplazo de la aorta. En pacientes con cirugía asociada (coronaria, reparación mitral/tricúspide) fue de 1/77 (1,3%). Durante el seguimiento murieron 12 pacientes (supervivencia a los 10 años: 95%). Las libertades de reoperación y de sustitución valvular a los 10 y 15 años fueron del 80% y 77% y del 86% y 83%, respectivamente. La libertad de reoperación a los 10 años fue superior en el reemplazo de la raíz (86%) o la aorta tubular (84%) en comparación con la reparación aislada (74%; p = 0,005). La libertad de cualquier complicación relacionada con la válvula fue del 80% y 77% a los 10 y 15 años, respectivamente, y fue mejor para reparación incluyendo "remodelación de la raíz" (87% y 82%) que para reparación aislada (77% y 77%; p = 0,04). Conclusiones: La reparación de la válvula aórtica bicúspide es un procedimiento seguro y duradero, con una incidencia baja de "complicaciones relacionadas con la válvula" a mediano y a largo plazos.

Introduction: Bicuspid aortic valve is the most common congenital heart disease. Traditionally, aortic valve replacement has been the approach for patients requiring surgery. After introduction of the bicuspid aortic valve repair concept, our group began reproducing these techniques, which have been standardized and homogeneously applied at our institutions. Objectives: The aim of this study was to review the conjoint experience of three centers and show the mid- and long-term results of bicuspid aortic valve repair. Methods: Between October 1995 and February 2013, 666 patients with bicuspid aortic valve underwent surgery for aortic regurgitation and/or aortic aneurysm. Isolated aortic regurgitation was present in 254 patients, and 412 had aortic aneurysm or dissection. The valve was reconstructed in all the patients (isolated valve repair in 254, "remodelling of the aortic root" in 281, remodelling of the sinotubular junction in 129 and "reimplantation" technique in 2). Results: Mortality was 3/666 (0.5%): 1/254 (0.4%) after isolated valve repair and 2/410 (0.5%) after valve repair plus aortic replacement. In patients with combined procedures (coronary revascularization or mitral/tricuspid valve repair), mortality was 1/77 (1.3%). During follow-up, 12 patients died (10-year survival: 95%). Freedom from reoperation and from aortic valve replacement at 10 and 15 years were 80% and 77%, and 86% and 83%, respectively Freedom from reoperation at 10 years was higher with aortic root (86%) or tubular aorta (84%) replacement, compared with isolated valve repair (74%; p = 0.005). Freedom from any valve-related complication was 80% and 77% at 10 and 15 years, respectively, and was better for valve repair including "remodelling of the aortic root" (87% and 82%) than for isolated repair (77% and 77%; p = 0.04). Conclusions: Bicuspid aortic valve repair is a safe, long-lasting procedure, with a low incidence of mid- and long-term "valve-related complications".

Selection of reference genes for quantitative real time PCR (qPCR) assays in tissue from human ascending aorta.

Dilatation of the ascending aorta (AAD) is a prevalent aortopathy that occurs frequently associated with bicuspid aortic valve (BAV), the most common human congenital cardiac malformation. The molecular mechanisms leading to AAD associated with BAV are still poorly understood. The search for differentially expressed genes in diseased tissue by quantitative real-time PCR (qPCR) is an invaluable tool to fill this gap. However, studies dedicated to identify reference genes necessary for normalization of mRNA expression in aortic tissue are scarce. In this report, we evaluate the qPCR expression of six candidate reference genes in tissue from the ascending aorta of 52 patients with a variety of clinical and demographic characteristics, normal and dilated aortas, and different morphologies of the aortic valve (normal aorta and normal valve n = 30; dilated aorta and normal valve n = 10; normal aorta and BAV n = 4; dilated aorta and BAV n = 8). The expression stability of the candidate reference genes was determined with three statistical algorithms, GeNorm, NormFinder and Bestkeeper. The expression analyses showed that the most stable genes for the three algorithms employed were CDKN1ß, POLR2A and CASC3, independently of the structure of the aorta and the valve morphology. In conclusion, we propose the use of these three genes as reference genes for mRNA expression analysis in human ascending aorta. However, we suggest searching for specific reference genes when conducting qPCR experiments with new cohort of samples.