Common Congenital Cardiac Abnormality Research Articles

Enhanced expression of iNOS is associated with aortic valve stenosis in patients with bicuspid aortic valve

Abstract Background A congenital bicuspid aortic valve (BAV) is one of the most common congenital cardiac abnormalities, with a prevalence estimated between 0.5% and 2%. Aortic valve stenosis (AS) is the most common complication in patients with BAV. The mechanisms responsible for the rapid progression of AS in patients with BAV relative to those with a tricuspid aortic valve (TAV) are unknown. A previous study showed that the pathogenesis of AS in patients with BAV is associated with a more aggressive inflammatory process, with increased macrophage infiltration and neo-vascularization when compared with that seen in patients with TAV. A considerable number of human diseases have an inflammatory component, and a key mediator of immune activation and inflammation is inducible nitric oxide synthase (iNOS). Overexpressed iNOS has been implicated in the pathogenesis of numerous conditions, including coronary plaque destabilization. To elucidate the role of iNOS in the aortic valve of patients with AS, we carried out an immunohistochemical study of the presence of iNOS in aortic valve specimens from patients with AS with either TAV or BAV. Methods Frozen aortic valve samples were obtained surgically from patients with AS with TAV (n=34) or BAV (n=34), and stained with antibodies against macrophages, microvessels, iNOS and 4-hydroxy-2-nonenal (4-HNE), an index of lipid peroxidation. The immunoreactivity of macrophages, microvessels, iNOS and 4-HNE was quantified using computer-aided polarimetry. Double immunostaining was also performed to identify cell types that stained positive for iNOS. Results Quantitative analysis demonstrated that macrophage-, iNOS-, and 4-HNE-positive areas, as well as the number of microvessels, were significantly higher in patients with AS with BAV than with TAV (macrophages, P<0.001; microvessels, P<0.05; 4-HNE, P<0.05; iNOS, P<0.001). The iNOS-positive area was positively correlated with the 4-HNE-positive area (R=0.43, P<0.0001). Double immunostaining for both iNOS and macrophages identified iNOS-positive cells as macrophages. Conclusions These findings suggest that accumulation of iNOS in macrophages may increase oxidative stress and contribute to the rapid progression of AS in patients with BAV.

Patent Foramen Ovale Closure in a Nonagenarian With Platypnoea-Orthodeoxia Syndrome

Patent foramen ovale (PFO) is a common congenital cardiac abnormality that affects one-quarter of the general population. Hypoxaemia, because of large right-to-left shunt, is a rare complication of PFO and occurs under exceptional physiological conditions. Case: This 90-year-old lady presented with progressive dyspnoea over several months. At presentation to hospital, she was hypoxaemic with pO2 of 53 mmHg and oxygen saturation of 89% despite 15L of oxygen via a mask. While lying supine for a computed tomography pulmonary angiogram (CTPA), it was noted that her oxygen saturation normalised. The CTPA excluded pulmonary embolus and intrapulmonary vascular anomaly. Intermittent intracardiac shunt was suspected and confirmed on formal shunt testing with a shunt fraction calculated at 32%. Transthoracic echocardiogram and cardiac CT failed to demonstrate an intracardiac shunt. Transoesophageal echocardiogram confirmed a PFO with dynamic right-to-left shunting on colour Doppler and with agitated saline. She underwent percutaneous closure with a 25-mm Amplatzer PFO Occluder, with a good procedural result and resolution of her symptoms. At the 2-month follow-up she remained well with no breathlessness and no device-related complications. This case illustrates an unusual cause of platypnoea-orthodeoxia syndrome due to PFO in a nonagenarian. It was hypothesised that a prominent Eustachian valve, and anatomical factors including enlarged tortuous aorta and pectus excavatum, had gradually progressed over time, distorting the cardiac anatomy, and contributing to significant shunting. Percutaneous PFO closure resulted in immediate symptomatic benefit.

Proximal Descending Thoracic Aorta Removal of a Coarctation Stent With Aortic Root Replacement

Coarctation of the aorta is a common congenital cardiac abnormality, largely diagnosed early in life. Many patients undergo surgical intervention, and up to half of them will require reintervention at some point. This study presents a 27-year-old man with a history of a bicuspid aortic valve and aortic coarctation previously treated with endovascular stenting at 16 years of age. He subsequently developed an aortic root aneurysm with mild residual coarctation with a post-stenotic dilatation. The purpose of this poster is to outline a novel technique for operative repair of an adult coarctation with explantation of a thoracic stent graft, with an open aortic repair of an aortic coarctation with aortic root replacement, using 27/29mm On-X mechanical valved conduit.

NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 Genetic Variations are Associated with Ventricular Septal Defect in the Chinese Tibetan Population Through Whole-Exome Sequencing.

Ventricular septal defect (VSD) is the most common congenital cardiac abnormality in children and the second most common in adults. This study aimed to explore the potentially causative genes in VSD patients in the Chinese Tibetan population, and to provide a theoretical basis for the genetic mechanism of VSD. Peripheral venous blood was collected from 20 VSD subjects, and whole-genome DNA was extracted. High-throughput sequencing was performed on qualified DNA samples using whole-exome sequencing (WES) technology. After filtering, detecting, and annotating qualified data, single nucleotide variations (SNVs) and insertion-deletion (InDel) markers were analyzed, and data processing software such as GATK, SIFT, Polyphen, and MutationTaster were used for comparative evaluation and prediction of pathogenic deleterious variants associated with VSD. A total of 4793 variant loci, including 4168 SNVs, 557 InDels and 68 unknown loci and 2566 variant genes were obtained from 20 VSD subjects through bioinformatics analysis. According to the screening of the prediction software and database, the occurrence of VSD was predicted to be associated with five inherited pathogenic gene mutations, all of which were missense mutations, including NOTCH2 (c.1396C >A:p.Gln466Lys), ATIC (c.235C >T:p.Arg79Cys), MRI1 (c.629G >A:p.Arg210Gln), SLC6A13 (c.1138G >A:p.Gly380Arg), ATP13A2 (c.1363C >T:p.Arg455Trp). This study demonstrated that NOTCH2, ATIC, MRI1, SLC6A13, ATP13A2 gene variants were potentially associated with VSD in Chinese Tibetan population.

Recent progress in patent foramen ovale and related neurological diseases: A narrative review.

Patent foramen ovale (PFO) is a common congenital cardiac abnormality when the opening of the interatrial septum is not closed in adulthood. This abnormality affects 25% of the general population. With the development of precision medicine, an increasing number of clinical studies have reported that PFO is closely related to various neurological diseases such as stroke, migraine, obstructive sleep apnea, and decompression syndrome. It has also been suggested that PFO closure could be effective for preventing and treating these neurological diseases. Therefore, increasing attention has been given to the prevention, diagnosis, and treatment of PFO-related neurological diseases. By reviewing existing literature, this article focuses on the pathogenesis, epidemiology, and clinical characteristics of PFO-related neurological diseases, as well as the prevention and treatment of different neurological diseases to discuss, and aims to provide current progress for this field and decision-making evidence for clinical practice.

Evaluation of left atrial and left ventricular functions in patients with Wolff-Parkinson-White syndrome before and after radiofrequency catheter ablation using three-dimensional speckle tracking echocardiography.

Wolff-Parkinson-White (WPW) syndrome is one of the most common congenital cardiac abnormalities among ventricular pre-excitation syndromes. Radiofrequency catheter ablation (RFCA) treatment of accessory pathways (APs) in WPW patients is an established curative therapy restoring normal atrioventricular conduction. We have not encountered any studies evaluating both the LA and LV functions of these patients before and after RFCA with three dimensional-speckle tracking echocardiography (3D-speckle tracking echocardiography (STE)). The purpose of the current study was to assess the LA and LV functions in patients with WPW syndrome before and after RFCA using 3D-STE. A total of 21 patients with WPW syndrome who had been scheduled for RFCA were prospectively recruited for this study. 3D-STE examinations of the patients were performed 12-24h before ablation and 1 month after ablation. The LV-global longitudinal strain (LV-GLS) and LV-global circumferential strain (LV-GCS) were significantly depressed in the pre-RFCA WPW group than in the control group (-14.3±2.1vs. -21.5±2.2, p<.001; -12.6±1.8vs. -20.4±1.8, p<.001, respectively). The left atrial strain-reservoir (LAS-r) and LAS-active were significantly decreased in the pre-RFCA WPW group than in the control group (31.9±2.4vs. 48.8±2.6, p<.001; 11.7±2vs. 26.5±2.1, p<.001, respectively). The LV-GLS, LV-GCS, LAS-r, and LAS-active values improved after RFCA compared to before. The results of our study indicated that there are subclinical impairments in LV and LA myocardial dynamics in the apparently healthy WPW patients, and these deteriorations improve after RFCA of AP.

Infective endocarditis in adults with congenital heart disease – 11 years data from Hungary

Abstract Background Despite recent preventive strategies and advances in antimicrobial and surgical treatment the incidence and mortality rate of infective endocarditis (IE) remains high in adult Congenital Heart Disease (ACHD) patients. Purpose The aim of our retrospective study was to assess the clinical and microbiological characteristics, inhospital and one year mortality rates of ACHD patients admitted with IE in our tertiary referral hospital between 2010 and 2020. Methods Definitive diagnosis of IE were in agreement with modified Duke's criteria. Inhospital baseline data and up to one year follow-up data were collected from the hospital records. ACHD patients were classified based on their lesion severity (ESC guideline classification). Survival data and mortality predictors were analysed by Kaplan-Meier estimator and by uni- and multivariate model. Results 60 cases had been treated with IE. Mean age was 37±11.3 years (18–69), and most of them (76.6%, n=46) were men. ACHD complexity was as following: simple 66.7% (n=40), moderate 20% (n=12) and severe 13.3% (n=8). The most common pre-existing congenital cardiac abnormality was bicuspidal aortic valve seen in 52% (n=31) of cases. Sixty four percent (n=37) of patients had previous heart surgery (n=16, artificial heart valve surgery). Majority of patients had a left sided valve endocarditis (85%, n=51). IE related hospital stay was mean 28±9 days. Infection route was presumed in 30% of patients (n=18), they had an invasive procedure within 6 months preceding the IE diagnosis. Besides common bacterinemia caused by Staphylococcus (33%, n=20) and Streptococcus (25%, n=15), 18% (n=11) of patients had a negative blood culture. IE affected 36 patients with a native valve, and all 16 with an artificial valve. Seventy seven percent of patients required surgical intervention, immediate or urgent surgery in 22 and elective in 24 patients. Overall inhospital mortality was 13%, the majority 5 out of 8 patients having an immediate/emergent surgical intervention. IE was complicated by acute heart failure in 17 (28%) and by stroke in 4 (6.7%) patients. During one year follow-up 21 patients (38%) remained with chronic heart failure, and 3 more died. There was no significant difference in mortality between ACHD complexity groups, and no significant predictors of mortality were found. Conclusion The most common ACHD lesion affected by IE was bicuspid aortic valve. Two-third of patients required surgical intervention, those with immediate/emergent surgery having a 22% early mortality rate. ACHD complexity was not related to early or late outcome in this population. Funding Acknowledgement Type of funding sources: None.

Risk of Perioperative Stroke in Patients With Patent Foramen Ovale: A Systematic Review and Meta-analysis.

Patent foramen ovale (PFO) is a common congenital cardiac abnormality. Risk of stroke increases perioperatively, but the association of PFO with perioperative stroke risk remains unclear. We conducted a systematic review to inform the risk of perioperative stroke in patients with PFO undergoing surgery. Embase, MEDLINE, and Cochrane databases were searched from inception to January 2020. We described methods used for establishing PFO and perioperative stroke diagnosis. We conducted meta-analyses to obtain pooled estimates for risk of stroke in patients with and without PFO in different surgical populations. Ten articles with a total of 20,858,011 patients met the eligibility criteria. Prevalence of PFO ranged from 0.06% to 1.4% based on International Classification of Diseases (ICD)-code diagnosis and from 10.4% to 40.4% based on echocardiography diagnosis. Perioperative stroke was observed in 0% to 25% of patients with PFO, and 0% to 16.7% without PFO. Studies that used echocardiography to diagnose PFO found no association between PFO and perioperative stroke. Studies that used ICD codes found strong association but were highly heterogeneous. PFO was not associated with a risk of perioperative stroke in cardiac and transplantation surgeries. While the adjusted odds ratios for stroke were substantial for orthopaedic, general, genitourinary, neurologic, and thoracic surgeries (with PFO status established based on ICD codes), data heterogeneity and quality of data create significant uncertainty. In conclusion, PFO is likely a risk factor for perioperative stroke in selected types of surgeries. However, this is based on very low-quality evidence. Rigorous prospective studies are needed to further investigate this relationship.

Bicuspid Aortic Valves: an Up-to-Date Review on Genetics, Natural History, and Management.

Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality. It has a wide spectrum of clinical manifestations including aortic regurgitation (AR), aortic stenosis, and an associated aortopathy with a small but increased risk of aortic dissection. This review describes current knowledge of BAV, from anatomy and genetics to a discussion of multifaceted strategies utilized in the management of this unique patient population. This review will also highlight critical knowledge gaps in areas of basic and clinical research to enhance further understanding of this clinical entity. The current knowledge regarding pathophysiologic mechanisms, screening, and surveillance guidelines for BAV and the associated aortopathy is discussed. We also discuss current management techniques for aortic valve repair versus replacement, indications for aortic surgery (root or ascending aorta), and the emergence of the Ross procedure as a viable management option not only in children, but also in adolescents and adults. The varied clinical phenotype of the BAV, resulting in its specific complex hemodynamic interactions, renders it an entity which is separate and distinct from the tricuspid aortic valve pathologies. While various aortic histopathologic and protein alterations in BAV patients have been described, it remains unclear if these changes are causal or the result of hemodynamic alterations imposed by sheer stress on the intrinsically dysfunctional BAV. Medical management for patients with BAV with AS, AI, or dilated aortic roots/ascending aortas remains challenging and needs further investigation. More than 50% of patients with BAV will undergo AVR during their lifetime, and more than 25% of patients with BAV undergo aortic surgery performed for dilation of the aortic root or ascending aorta, often concurrently with AVR. The search for the ultimate genetic or epigenetic cause of the different bicuspid phenotypes will ultimately be facilitated by the next-generation sequencing tools that allow for study of large populations at low cost. Improvements in diagnostic and stratification criteria to accurately risk assess BAV patients are critical to this process.

Aortic Dilatation in Patients With Bicuspid Aortic Valve.

Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality. BAV aortic dilatation is associated with an increased risk of adverse aortic events and represents a potentially lethal disease and hence a considerable medical burden. BAV with aortic dilatation warrants frequent monitoring, and elective surgical intervention is the only effective method to prevent dissection or rupture. The predictive value of the aortic diameter is known to be limited. The aortic diameter is presently still the main reference standard for surgical intervention owing to the lack of a comprehensive understanding of BAV aortopathy progression. This article provides a brief comprehensive review of the current knowledge on BAV aortopathy regarding clinical definitions, epidemiology, natural course, and pathophysiology, as well as hemodynamic and clinically significant aspects on the basis of the limited data available.

The evolving role of echocardiography in the assessment of patent foramen ovale in patients with left-side thromboembolism.

Patent foramen ovale (PFO) is the most common congenital cardiac abnormality found approximately in 25% of the adult population The pathophysiological role of paradoxical embolization through the PFO in ischemic stroke is well established. "Self-expanding double disk" and, more recently, suture-based "deviceless" systems are used for PFO closure in the setting of secondary prevention after ischemic stroke likely related to paradoxical embolization. Ultrasound plays a significant role in PFO assessment, indication to treatment, intra-procedural guidance, and follow-up for those undergoing PFO closure. Three different techniques are frequently used for these purposes: transesophageal echocardiography, transthoracic echocardiogram, and transcranial Doppler. In this review, advantages and limits of these techniques are discussed in detail to improve our skills in detection and treatment of this important condition by using ultrasound.

Assessment of valvular dysfunction and aortic involvement in patients with bicuspid aortic valve: Echocardiographic study

Bicuspid aortic valve is the most common congenital cardiac abnormality, affecting approximately 0.5–2% of the general population, of which 75% are male and is defined by the presence of two abnormal leaflets, usually unequal in size. A prospective sign centre study had been performed in the department of Cardiology, Ibn-Rochd university hospital, to assess the evolution of valvular and aortic involvement in adults patients with bicuspid aortic valve. A total of 106 patients with bicuspid aortic valve were included during a follow-up of 10 years. Aortic dimensions and other echocardiographic parameters were obtained from the echocardiography database of department. Patients with bicuspid aortic valve were mainly male (76.4%), with a mean age of 49 ± 15 years and a significant proportion of hypertensive patients (50.9%). We notice a majoration of the number of patients with aortic stenosis over time ( P < 0.001), with an involvement of transthoracic echocardiography parameters of aortic stenosis, a decrease of the aortic valve area, indexed or not, an increase of peak velocity and mean gradient, this progression was significantly higher ( P = 0.0025) in subjects with aortic stenosis at inclusion: 16 cm/s/year against 4.6 cm/s/y and an mean gradient of 3.5 mmHg/year against 0.6 mmHg/y, whereas the progression of dilatation of sinus of Valsalva and tubular ascending aorta was also more important in patients with aortic stenosis at inclusion compared with those who had not aortic diameters between the 1st and the last control sinus of valsalva: 0.17–0.3 mm/year, tubular ascending aorta: 0.32–0.6 mm/year. A significant progression of aortic diameter was observed in patients with a small aorta at inclusion compared of others ( Table 1 ). This study reinforces the fact that clinical and echographic surveillance of these patients, even if they are asymptomatic, thus fundamental and necessary to better prevent complications.

Lung Ultrasound Score Predicts the Extravascular Lung Water Content in Low-Birth-Weight Neonates with Patent Ductus Arteriosus.

BackgroundPatent ductus arteriosus (PDA) is a common congenital cardiac abnormality in premature infants. In low-birth-weight infants weighing less than 2500 g, if the PDA continues to open, abnormal circulation hemodynamics and pulmonary edema may occur. This study aimed to investigate the role of lung ultrasound score in the assessment of pulmonary edema in low-weight neonates with PDA.Material/MethodsTwo hundred and twenty-one neonates with low birth weight were selected as the subjects, children with PDA as the observation group, and children with closed ductus arteriosus as the control group. On the fourth postnatal day, lung ultrasound examination and 6-segment lung ultrasound scoring were performed.ResultsAll 221 infants (94 in the observation group, 127 controls) underwent ultrasound examinations of the lungs. Intergroup differences in gestational age, birth weight, length of hospital stay, and left ventricular ejection fraction were not statistically significant. There was a significant difference in lung ultrasound score (t=0.005, P=0.000) and aortic root ratio to left atrial (t=0.085, P=0.000), which was negatively correlated with gestational age (r=−0.235, P=0.000) and positively correlated with PDA diameter (r=0.261, P=0.011).ConclusionsLow-birth-weight children often have PDA. Its continued opening changes the circulation hemodynamics in children. Lung ultrasound score can semi-quantitatively evaluate the extravascular lung water content, identifying the need to intervene and follow up the hemodynamic significance of PDA over time.

Thoracic Aortic Aneurysm Growth in Bicuspid Aortic Valve Patients: Role of Aortic Stiffness and Pulsatile Hemodynamics.

BackgroundBicuspid aortic valve (BAV) is the most common congenital cardiac abnormality. A thoracic aortic aneurysm (TAA) is present in ≈50% of BAV patients, who also have an 8‐fold higher risk of aortic dissection than the general population. Because the health of the aorta is directly reflected in its stiffness and pulsatile hemodynamics, we hypothesized that measures of aortic stiffness and arterial load would be associated with TAA growth in BAV.Methods and ResultsTwenty‐nine unoperated participants with TAA due to BAV who had serial imaging were recruited. Aortic stiffness and steady and pulsatile arterial load were evaluated with validated methods that integrate arterial tonometry with echocardiography. TAA growth was assessed retrospectively based on available imaging, blinded to hemodynamic status. Multivariable linear regression assessed associations of aortic stiffness and hemodynamic variables with TAA growth, adjusting for potential confounders. Overall, 66% of participants were men. Mean±SD for age, baseline aneurysm size, growth rate, and follow‐up time were 57.2±8.3 years, 46.9±3.6 mm, 0.75±0.81 mm/y, and 2.9±3.3 years, respectively. We found that greater aortic stiffness (β±SE for carotid‐femoral pulse wave velocity: 0.30±0.13. P=0.03) and aortic characteristic impedance (β±SE: 0.46±0.18, P=0.02), as well as lower total arterial and proximal aortic compliance (β±SE: −0.44±0.21, P=0.05, and −0.63±0.16, P=0.001, respectively) were independently associated with faster aneurysm growth.ConclusionsIn patients with TAA due to BAV, measures of greater aortic stiffness and pulsatile arterial load indicate an association with accelerated aneurysm expansion. Assessing arterial hemodynamics may be useful for risk stratification and disease monitoring in TAA patients with BAV.

THORACIC AORTIC ANEURYSM GROWTH IN PATIENTS WITH BICUSPID AORTIC VALVES: ROLE OF AORTIC STIFFNESS AND PULSATILE HEMODYNAMICS

Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality, and the second most common etiology for thoracic aortic aneurysm (TAA) formation. Among BAV patients, risk of aortic dissection is increased 8-fold, and 25-year risk of aortic surgery is 25%. However, there are no clinical predictors of aneurysm growth for risk stratification. Since the health of the aortic wall is directly reflected in its stiffness, which increases pulsatile hemodynamic load due to impairment of the aorta’s pressure buffering function, we evaluated whether measures of aortic stiffness and hemodynamic load are associated with TAA growth in patients with BAV. Twenty nine participants with TAA due to BAV who had serial imaging were recruited. Aneurysm size was measured systematically by an imaging cardiologist blinded to hemodynamics, and growth rate was calculated in mm/year. Central arterial hemodynamics were non-invasively determined with validated methods that integrate arterial tonometry with echocardiography, yielding measures of aortic stiffness (aortic pulse wave velocity, aPWV), steady (systemic vascular resistance) and pulsatile hemodynamic load [aortic characteristic impedance (Zc), proximal aortic (PAC) and total arterial (TAC) compliances, central systolic (cSBP) and pulse pressures, forward (Pf) and reflected pressure wave amplitudes]. Spearman correlation coefficients were calculated between TAA growth rate and brachial blood pressure, as well as the aforementioned central hemodynamic measures. Multivariable linear regression adjusted for potential confounders (Table 1 legend) assessed the independent associations of hemodynamic variables with TAA growth. Sixty six percent of participants were men. Mean±standard deviation (SD) age, baseline aneurysm size and follow-up time were 57.2±8.3 years, 46.9±3.6 mm and 2.9±3.3 years, respectively. There were significant correlations between several measures of aortic stiffness and pulsatile arterial load with TAA growth (Table1, top). There were no significant correlations between brachial blood pressure parameters or steady hemodynamic load with TAA growth (P>0.05 for each). In multivariable linear regression, measures of aortic stiffness (aPWV) and pulsatile hemodynamic load (Zc, PAC, TAC) remained independently associated with aneurysm growth (Table 1, bottom). Other hemodynamic measures were not independently associated with TAA growth. In patients with TAA due to BAV, greater aortic stiffness and central pulsatile hemodynamic load are associated with faster aneurysm growth; while brachial blood pressure and steady hemodynamic load are not. Our findings suggest that evaluating aortic stiffness and pulsatile arterial load could be useful for risk stratification of subjects with TAA due to BAV, and may provide a therapeutic target for this disease.

Candidate plasma biomarkers for predicting ascending aortic aneurysm in bicuspid aortic valve disease

BackgroundBicuspid aortic valve (BAV) disease is the most common congenital cardiac abnormality affecting 1–2% of the population and is associated with a significantly increased risk of ascending aortic aneurysm. However, predicting which patients will develop aneurysms remains a challenge. This pilot study aimed to identify candidate plasma biomarkers for monitoring ascending aortic diameter and predicting risk of future aneurysm in BAV patients.MethodsPlasma samples were collected pre-operatively from BAV patients undergoing aortic valve surgery. Maximum ascending aortic diameter was measured on pre-operative transoesophageal echocardiography. Maximum diameter ≥ 45 mm was classified as aneurysmal. Sequential Window Acquisition of all THeoretical Mass Spectra (SWATH-MS), an advanced mass spectrometry technique, was used to identify and quantify all proteins within the samples. Protein abundance and aortic diameter were correlated using logistic regression. Levene’s test was used to identify proteins demonstrating low abundance variability in the aneurysmal patients (consistent expression in disease), and high variability in the non-aneurysmal patients (differential expression between ‘at risk’ and not ‘at risk’ patients).ResultsFifteen plasma samples were collected (seven non-aneurysmal and 8 aneurysmal BAV patients). The mean age of the patients was 55.5 years and the majority were female (10/15, 67%). Four proteins (haemoglobin subunits alpha, beta and delta and mannan-binding lectin serine protease) correlated significantly with maximal ascending aortic diameter (p < 0.05, r = 0.5–0.6). Five plasma proteins demonstrated significantly lower variability in the aneurysmal group and may indicate increased risk of aneurysm in non-aneurysmal patients (DNA-dependent protein kinase catalytic subunit, lumican, tetranectin, gelsolin and cartilage acidic protein 1). A further 7 proteins were identified only in the aneurysmal group (matrin-3, glucose-6-phosphate isomerase, coactosin-like protein, peptidyl-prolyl cis-trans isomerase A, golgin subfamily B member 1, myeloperoxidase and 2′-deoxynucleoside 5′-phosphate N-hydrolase 1).ConclusionsThis study is the first to identify candidate plasma biomarkers for predicting aortic diameter and risk of future aneurysm in BAV patients. It provides valuable pilot data and proof of principle that could be used to design a large-scale prospective investigation. Ultimately, a more affordable ‘off-the-shelf’ follow-on blood assay could then be developed in place of SWATH-MS, for use in the healthcare setting.

Endogenous Reference Genes for Gene Expression Studies on Bicuspid Aortic Valve Associated Aortopathy in Humans.

Bicuspid aortic valve (BAV) disease is the most common congenital cardiac abnormality and predisposes patients to life-threatening aortic complications including aortic aneurysm. Quantitative real-time reverse transcription PCR (qRT-PCR) is one of the most commonly used methods to investigate underlying molecular mechanisms involved in aortopathy. The accuracy of the gene expression data is dependent on normalization by appropriate housekeeping (HK) genes, whose expression should remain constant regardless of aortic valve morphology, aortic diameter and other factors associated with aortopathy. Here, we identified an appropriate set of HK genes to be used as endogenous reference for quantifying gene expression in ascending aortic tissue using a spin column-based RNA extraction method. Ascending aortic biopsies were collected intra-operatively from patients undergoing aortic valve and/or ascending aortic surgery. These patients had BAV or tricuspid aortic valve (TAV), and the aortas were either dilated (≥4.5cm) or undilated. The cohort had an even distribution of gender, valve disease and hypertension. The expression stability of 12 reference genes were investigated (ATP5B, ACTB, B2M, CYC1, EIF4A2, GAPDH, SDHA, RPL13A, TOP1, UBC, YWHAZ, and 18S) using geNorm software. The most stable HK genes were found to be GAPDH, UBC and ACTB. Both GAPDH and UBC demonstrated relative stability regardless of valve morphology, aortic diameter, gender and age. The expression of B2M and SDHA were found to be the least stable HK genes. We propose the use of GAPDH, UBC and ACTB as reference genes for gene expression studies of BAV aortopathy using ascending aortic tissue.

Three-Dimensional Evaluation of Aortic Valve Annular Shape in Children With Bicuspid Aortic Valves and/or Aortic Coarctation Compared With Controls

Bicuspid aortic valve (BAV) is the most common congenital cardiac abnormality, occurring in 1% to 2% of the general population. Adults with degenerative aortic valve (AV) disease have been shown to have an elliptical shaped AV annulus. The goal of this study was to investigate the shape of the aortic annulus in children with BAV, coarctation of the aorta (CoA) with or without BAV, and normal controls with trileaflet AVs using 3-dimensional echocardiography (3DE). We reviewed echocardiograms of children with isolated BAV (n= 40), CoA (n= 26), and controls (n= 40) that included 3DE of the AV. Eccentricity index (EI) was defined as the ratio between the smaller and larger annular dimension. ΔD was defined as the difference between the larger and smaller annular dimension. Patients with BAV had an eccentric AV annulus compared with controls (BAV EI 0.85 ± 0.05 and control EI 0.96 ± 0.03; p <0.001). Subjects with CoA also had a more eccentric annulus than controls regardless of AV morphology (CoA 0.84 ± 0.06; p <0.001). EI was not associated with somatic growth parameters or gender. Among all patients with BAV, AV dysfunction was associated with fusion of the right and noncoronary (R-N) cusps (p <0.001), but there was no association between valve dysfunction and EI. ΔD was higher in both the BAV and CoA groups compared with the control group (BAV 3.4 ± 1.9mm, CoA 2.8 ± 1.8mm, and control 0.6 ± 0.4mm; p <0.001 each). Although there was no significant correlation of ΔD with age in the control group during childhood, ΔD increased with age in the BAV and CoA groups. In conclusion, children with BAV and/or CoA have an elliptical shaped AV annulus by 3DE, which is independent of age, gender, or body surface area. AV annular eccentricity may lead to inaccurate measurement of AV annular size if measured by 2DE alone. Considering AV annular eccentricity when balloon sizing the annulus before valvuloplasty may help improve interventional results in some patients.

Type A aortic dissection in patients with bicuspid or tricuspid aortic valves: a retrospective comparative study in 288 Chinese patients

The propensity for aortic aneurysm and dissection bestows bicuspid aortic valves (BAVs), the most common congenital cardiac abnormality, a potentially lethal aspect and considerable clinical concern. In the present study, we attempted to better characterize BAV patients with acute type A aortic dissection (AAD). Data from 288 consecutive patients undergoing surgery for acute AAD between December 2007 and April 2012 at our institute were retrospectively collected. Patients were categorized into BAV (n = 30) and tricuspid aortic valve (n = 258) groups to investigate their clinical and prognostic features. BAV patients tended to have younger age, lower systolic blood pressure, higher rate of moderate-to-severe aortic stenosis and wider ascending aorta (all P < 0.05). The 30-day postoperative mortality was significantly higher among BAV patients (23.3 vs 8.1%, P = 0.016), with an elevated proportion of both cardiogenic deaths and complications. BAV patients who died during the follow-up period demonstrated higher incidence of aortic stenosis (57.1 vs 13.0%, P = 0.033), coronary artery ostium involvement (57.1 vs 4.3%, P = 0.006) and longer cardiopulmonary bypass time (190.7 ± 67.5 vs 140.3 ± 37.1 min, P = 0.035). BAV-associated dissection, as a unique subgroup of AAD, demonstrated strikingly high postoperative mortality in a Chinese population. Moderate-to-severe aortic stenosis and dissection involving coronary artery ostium might be associated with the adverse clinical outcomes among BAV patients.

Genotype–phenotype correlation in patients with bicuspid aortic valve and aneurysm

Bicuspid aortic valve is the most common congenital cardiac abnormality, occurring in 1% to 2% of the population, and often associates with ascending aortic aneurysm. Based on familial studies, bicuspid aortic valve with aneurysm segregates in an autosomal dominant manner with incomplete penetrance. NOTCH1 mutations have been reported in 6 families with prominent valve calcification and dysfunction and low penetrance of aneurysm. We sought to determine the contribution of NOTCH1 mutations to the more common phenotype of highly penetrant aneurysms with low penetrance of bicuspid aortic valve and with rare valve calcification or dysfunction. All exons and splice junctions of NOTCH1 were sequenced in probands from 13 affected families presenting with bicuspid aortic valve with ascending aortic aneurysm in the absence of valve calcification. In addition, mutation analysis was performed on a single individual with aneurysm and calcified tricuspid aortic valve. Sequences were aligned and compared with the reference genomic sequence. Corroborating previous studies, analysis of the single sporadic patient with calcified aortic valve in the presence of ascending aortic aneurysm revealed a novel heterozygous missense mutation in NOTCH1 resulting in a nonsynonymous amino acid substitution (p.T1090S, c.C3269G) of an evolutionarily conserved residue. This change was not observed in controls. In contrast, we did not identify any pathologic NOTCH1 mutations in the 13families segregating noncalcified bicuspid aortic valve with highly penetrant aortic aneurysm. These data suggest that there are phenotypic differences that distinguish families with and without NOTCH1 mutations, indicating a genotype-phenotype correlation with potential implications for patient diagnosis, counseling, and management.